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1.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
2.  Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data 
PLoS Medicine  2013;10(11):e1001552.
Cécile Viboud and colleagues describe epidemiological patterns of influenza incidence across China to support the design of a national vaccination program.
Please see later in the article for the Editors' Summary
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.
Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%–151%] in the north versus 37% [95% CI 27%–47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N–31.3°N, slope of latitudinal gradient with latitude −0.016 [95% CI −0.025 to −0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.
Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.
Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.
What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.
What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001552.
This study is further discussed in a PLOS Medicine Perspective by Steven Riley
The UK National Health Service Choices website provides information for patients about seasonal influenza and about influenza vaccination
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza surveillance and monitoring
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination; its website contains a short video about personal experiences of influenza.
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
Information about the Chinese National Influenza Center, which is part of the Chinese Center for Disease Control and Prevention: and which runs influenza surveillance in China, is available (in English and Chinese)
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
A recent PLOS Pathogens Research Article by James D. Tamerius et al. investigates environmental predictors of seasonal influenza epidemics across temperate and tropical climates
A study published in PLOS ONE by Wyller Alencar de Mello et al. indicates that Brazil, like China, requires staggered timing of vaccination from Northern to Southern states to account for different timings of influenza activity.
doi:10.1371/journal.pmed.1001552
PMCID: PMC3864611  PMID: 24348203
3.  Influenza Vaccination in Cancer Patients Undergoing Systemic Therapy 
BACKGROUND
Cancer patients often experience preventable infections, including influenza A and B. These infections can be a cause of significant morbidity and mortality. The increased risk of infection may be because of either cancer itself or treatment-induced immunosuppression.1 Influenza immunization has been shown to decrease the risk of influenza infection in patients with intact immunity.2 In cancer patients, active immunization has been shown to confer protective immunity against several infections at similar rates to healthy individuals, which has translated into decreased duration and severity of infection and potentially improved morbidity and mortality.3
OBJECTIVES
To assess the efficacy of influenza vaccination in stimulating immunological response in patients with cancer during chemotherapy compared to control groups.
To assess the efficacy of influenza vaccination in preventing confirmed influenza and influenza-like illness and/or stimulating immunological response in children with cancer treated with chemotherapy, compared to placebo, no intervention, or different dosage schedules.
To determine the adverse effects associated with influenza vaccination in patients with cancer.
SEARCH METHODS
We searched MEDLINE/PubMed database for articles published from 1964 to 2013 using the search terms “cancer,” “adult,” “influenza vaccination,” and “chemotherapy.”
SELECTION CRITERIA
We included studies based on systematic sampling with defined clinical criteria irrespective of the vaccination status of cancer patients. Studies measure the serological response or clinical response to compare between the study group and the control group. Studies assessed the inactivated influenza vaccines and live attenuated influenza vaccine (LAIV) protective serological reaction and the clinical outcomes after vaccination.
DATA COLLECTION AND ANALYSIS
Two independent authors assessed the methodological quality of included studies and extracted data.
MAIN RESULTS
We included 16 studies (total number of participants = 1,076). None of the included studies reported clinical outcomes. All included studies reported on influenza immunity and adverse reaction on vaccination. We included 6 solid tumor studies and 10 hematological studies. In 12 studies, the serological response to influenza vaccine was compared in patients receiving chemotherapy (n = 425) versus those not receiving chemotherapy (n = 376). In three studies, the serological responses to influenza vaccination in patients receiving chemotherapy are compared to that in healthy adult. Measures used to assess the serological responses included a four-fold rise increase in antibody titer development of hemagglutination inhibition (HI) titer >40, and pre- and post-vaccination geometric mean titers (GMTs). Immune responses in patients receiving chemotherapy were consistently weaker (four-fold rise of 17–52%) than in those who had completed chemotherapy (50–83%) and healthy patients (67–100%). Concerning adverse effects, oncology patients received influenza vaccine, and the side effects described were mild local reactions and low-grade fever. No life-threatening or persistent adverse effects were reported.
AUTHORS’ CONCLUSION
Patients with solid and some of hematological tumors are able to mount a serological response to influenza vaccine, but it remains unclear how much this response protects them from influenza infection or its complications. Meanwhile, influenza vaccine appears to be safe in these patients. While waiting results of randomized controlled trials to give us more details about the clinical benefits of the influenza vaccination, the clinicians should consider the currently proved benefits of influenza vaccination on management of the cancer patients undergoing systematic chemotherapy such as decrease in the duration and severity of the of the disease, and significant decrease in influenza-associated morbidity and mortality in these high-risk patients.3
doi:10.4137/CMO.S13774
PMCID: PMC4011725  PMID: 24855405
influenza vaccination; cancer patients; chemotherapy
4.  The Effect of Universal Influenza Immunization on Mortality and Health Care Use 
PLoS Medicine  2008;5(10):e211.
Background
In 2000, Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free influenza vaccines for the entire population aged 6 mo or older. Influenza immunization increased more rapidly in younger age groups in Ontario compared to other Canadian provinces, which all maintained targeted immunization programs. We evaluated the effect of Ontario's UIIP on influenza-associated mortality, hospitalizations, emergency department (ED) use, and visits to doctors' offices.
Methods and Findings
Mortality and hospitalization data from 1997 to 2004 for all ten Canadian provinces were obtained from national datasets. Physician billing claims for visits to EDs and doctors' offices were obtained from provincial administrative datasets for four provinces with comprehensive data. Since outcomes coded as influenza are known to underestimate the true burden of influenza, we studied more broadly defined conditions. Hospitalizations, ED use, doctors' office visits for pneumonia and influenza, and all-cause mortality from 1997 to 2004 were modelled using Poisson regression, controlling for age, sex, province, influenza surveillance data, and temporal trends, and used to estimate the expected baseline outcome rates in the absence of influenza activity. The primary outcome was then defined as influenza-associated events, or the difference between the observed events and the expected baseline events. Changes in influenza-associated outcome rates before and after UIIP introduction in Ontario were compared to the corresponding changes in other provinces. After UIIP introduction, influenza-associated mortality decreased more in Ontario (relative rate [RR] = 0.26) than in other provinces (RR = 0.43) (ratio of RRs = 0.61, p = 0.002). Similar differences between Ontario and other provinces were observed for influenza-associated hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.69, ratio of RRs = 0.45, p < 0.001), and doctors' office visits (RR = 0.21 versus 0.52, ratio of RRs = 0.41, p < 0.001). Sensitivity analyses were carried out to assess consistency, specificity, and the presence of a dose-response relationship. Limitations of this study include the ecological study design, the nonspecific outcomes, difficulty in modeling baseline events, data quality and availability, and the inability to control for potentially important confounders.
Conclusions
Compared to targeted programs in other provinces, introduction of universal vaccination in Ontario in 2000 was associated with relative reductions in influenza-associated mortality and health care use. The results of this large-scale natural experiment suggest that universal vaccination may be an effective public health measure for reducing the annual burden of influenza.
Comparing influenza-related mortality and health care use between Ontario and other Canadian provinces, Jeffrey Kwong and colleagues find evidence that Ontario's universal vaccination program has reduced the burden of influenza.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. These epidemics occur because of “antigenic drift”: small but frequent changes in the viral proteins to which the human immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Immunization can boost this natural immunity and reduce a person's chances of catching influenza. That is, an injection of killed influenza viruses can be used to prime the immune system so that it responds quickly and efficiently when exposed to live virus. However, because of antigenic drift, for influenza immunization to be effective, it has to be repeated annually with a vaccine that contains the major circulating strains of the influenza virus.
Why Was This Study Done?
Public-health organizations recommend targeted vaccination programs, so that elderly people, infants, and chronically ill individuals—the people most likely to die from pneumonia and other complications of influenza—receive annual influenza vaccination. Some experts argue, however, that universal vaccination might provide populations with better protection from influenza, both directly by increasing the number of vaccinated people and indirectly through “herd immunity,” which occurs when a high proportion of the population is immune to an infectious disease, so that even unvaccinated people are unlikely to become infected (because infected people rarely come into contact with susceptible people). In this study, the researchers compare the effects of the world's first free universal influenza immunization program (UIIP), which started in 2000 in the Canadian province of Ontario, on influenza-associated deaths and health care use with the effects of targeted vaccine programs on the same outcomes elsewhere in Canada.
What Did the Researchers Do and Find?
Using national records, the researchers collected data on influenza vaccination, on all deaths, and on hospitalizations for pneumonia and influenza in all Canadian provinces between 1997 and 2004. They also collected data on emergency department and doctors' office visits for pneumonia and influenza for Ontario, Quebec, Alberta, and Manitoba. They then used a mathematical model to estimate the baseline rates for these outcomes in the absence of influenza activity, and from these calculated weekly rates for deaths and health care use specifically resulting from influenza. In 1996–1997, 18% of the population was vaccinated against influenza in Ontario whereas in the other provinces combined the vaccination rate was 13%. On average, since 2000—the year in which UIIP was introduced in Ontario—vaccination rates have risen to 38% and 24% in Ontario and the other provinces, respectively. Since the introduction of UIIP, the researchers report, influenza-associated deaths have decreased by 74% in Ontario but by only 57% in the other provinces combined. Influenza-associated use of health care facilities has also decreased more in Ontario than in the other provinces over the same period.
What Do These Findings Mean?
These findings are limited by some aspects of the study design. For example, they depend on the accuracy of the assumptions made when calculating events due specifically to influenza, and on the availability and accuracy of vaccination and clinical outcome data. In addition, it is possible that influenza-associated deaths and health care use may have decreased more in Ontario than in the other Canadian provinces because of some unrecognized health care changes specific to Ontario but unrelated to the introduction of universal influenza vaccination. Nevertheless, these findings indicate that, compared to the targeted vaccination programs in the other Canadian provinces, the Ontarian UIIP is associated with reductions in influenza-associated deaths and health care use, particularly in people younger than 65 years old. This effect is seen at a level of vaccination unlikely to produce herd immunity so might be more marked if the uptake of vaccination could be further increased. Thus, although it is possible that Canada is a special case, these findings suggest that universal influenza vaccination might be an effective way to reduce the global burden of influenza.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050211.
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Carline van den Dool and colleagues is also available
The Ontario Ministry of Health provides information on its universal influenza immunization program (in English and French)
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about the science of immunization, including a simple explanatory animation of immunity
doi:10.1371/journal.pmed.0050211
PMCID: PMC2573914  PMID: 18959473
5.  Immunogenicity and Safety of Influenza Vaccination in Systemic Lupus Erythematosus Patients Compared with Healthy Controls: A Meta-Analysis 
PLoS ONE  2016;11(2):e0147856.
Objective
To assess the immunogenicity and safety of influenza vaccine in patients with systemic lupus erythematosus (SLE).
Methods
Relevant articles were retrieved from electronic databases. Seroprotection rate, seroconversion rate and factors that increase antibody geometric mean titer (GMT) were used as indices to measure the immunogenicity. The safety of vaccine was assessed through monitoring adverse events, which included side effects and SLE exacerbations. We performed a meta-analysis of influenza vaccine seroprotection, seroconversion and adverse effects. SLE exacerbation after vaccination was comprehensively described. We used the Committee for Proprietary Medicinal Products (CPMP) guidelines to determine whether influenza can induce adequate immunogenicity in patients with SLE.
Results
Eighteen studies with 1966 subjects met the inclusion criteria. At least 565 of the subjects were patients with low-to-moderate SLE Disease Activity Index (SLEDAI) score or stable SLE disease. Compared with the general population, seroprotection rate in SLE patients was significantly decreased in patients with H1N1 [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.27–0.50] and H3N2 vaccination (OR = 0.48, 95% CI: 0.24–0.93), but not influenza B vaccination (OR = 0.55, 95% CI: 0.24–1.25). Seroconversion rate also significantly decreased in patients with H1N1 (OR = 0.39, 95% CI: 0.27–0.57) and influenza B (OR = 0.47, 95% CI: 0.29–0.76) vaccination, but not H3N2 vaccination (OR = 0.62, 95% CI: 0.21–1.79). However, the immunogenicity of influenza vaccine in SLE patients almost reached that of the CPMP guidelines. The OR for side effects (patients versus healthy controls) was 3.24 (95% CI: 0.62–16.76). Among 1966 patients with SLE, 32 experienced mild exacerbation of SLE and five had serious side effects for other reasons.
Conclusion
Influenza vaccine has moderate effect on protecting patients with SLE. The side effects of influenza vaccine are not serious and are manageable. With consideration of a higher risk of SLE exacerbation and a more severe course of infection among SLE patients, influenza vaccination should be promoted among SLE patients with a low-to-moderate SLEDAI score or stable disease.
doi:10.1371/journal.pone.0147856
PMCID: PMC4742052  PMID: 26845680
6.  Seasonal Influenza Vaccination for Children in Thailand: A Cost-Effectiveness Analysis 
PLoS Medicine  2015;12(5):e1001829.
Background
Seasonal influenza is a major cause of mortality worldwide. Routine immunization of children has the potential to reduce this mortality through both direct and indirect protection, but has not been adopted by any low- or middle-income countries. We developed a framework to evaluate the cost-effectiveness of influenza vaccination policies in developing countries and used it to consider annual vaccination of school- and preschool-aged children with either trivalent inactivated influenza vaccine (TIV) or trivalent live-attenuated influenza vaccine (LAIV) in Thailand. We also compared these approaches with a policy of expanding TIV coverage in the elderly.
Methods and Findings
We developed an age-structured model to evaluate the cost-effectiveness of eight vaccination policies parameterized using country-level data from Thailand. For policies using LAIV, we considered five different age groups of children to vaccinate. We adopted a Bayesian evidence-synthesis framework, expressing uncertainty in parameters through probability distributions derived by fitting the model to prospectively collected laboratory-confirmed influenza data from 2005-2009, by meta-analysis of clinical trial data, and by using prior probability distributions derived from literature review and elicitation of expert opinion. We performed sensitivity analyses using alternative assumptions about prior immunity, contact patterns between age groups, the proportion of infections that are symptomatic, cost per unit vaccine, and vaccine effectiveness. Vaccination of children with LAIV was found to be highly cost-effective, with incremental cost-effectiveness ratios between about 2,000 and 5,000 international dollars per disability-adjusted life year averted, and was consistently preferred to TIV-based policies. These findings were robust to extensive sensitivity analyses. The optimal age group to vaccinate with LAIV, however, was sensitive both to the willingness to pay for health benefits and to assumptions about contact patterns between age groups.
Conclusions
Vaccinating school-aged children with LAIV is likely to be cost-effective in Thailand in the short term, though the long-term consequences of such a policy cannot be reliably predicted given current knowledge of influenza epidemiology and immunology. Our work provides a coherent framework that can be used for similar analyses in other low- and middle-income countries.
Ben Cooper and colleagues use an age-structured model to estimate optimal cost-effectiveness of flu vaccination among Thai children aged 2 to 17.
Editors' Summary
Background
Every year, millions of people catch influenza, a viral disease of the airways. Most infected individuals recover quickly, but elderly people, the very young, and chronically ill individuals are at high risk of developing serious complications such as pneumonia; seasonal influenza kills about half a million people annually. Small but frequent changes in the influenza virus mean that an immune response produced one year by exposure to the virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed or live-attenuated (weakened) influenza viruses of the major circulating strains can reduce a person’s chance of catching influenza. Consequently, many countries run seasonal influenza vaccination programs that target elderly people and other people at high risk of influenza complications, and people who care for these individuals.
Why Was This Study Done?
As well as reducing the vaccinated person’s risk of infection, influenza vaccination protects unvaccinated members of the population by reducing the chances of influenza spreading. Because children make a disproportionately large contribution to the transmission of influenza, vaccination of children might therefore provide greater benefits to the whole population than vaccination of elderly people, particularly when vaccination uptake among the elderly is low. Thus, many high-income countries now recommend annual influenza vaccination of children with a trivalent live-attenuated influenza vaccine (LAIV; a trivalent vaccine contains three viruses), which is sprayed into the nose. However, to date no low- or middle-income countries have evaluated this policy. Here, the researchers develop a mathematical model (framework) to evaluate the cost-effectiveness of annual vaccination of children with LAIV or trivalent inactivated influenza vaccine (TIV) in Thailand. A cost-effectiveness analysis evaluates whether a medical intervention is good value for money by comparing the health outcomes and costs associated with the introduction of the intervention with the health outcomes and costs of the existing standard of care. Thailand, a middle-income country, offers everyone over 65 years old free seasonal influenza vaccination with TIV, but vaccine coverage in this age group is low (10%).
What Did the Researchers Do and Find?
The researchers developed a modeling framework that contained six connected components including a transmission model that incorporated infectious contacts within and between different age groups, a health outcome model that calculated the disability-adjusted life years (DALYs, a measure of the overall disease burden) averted by specific vaccination policies, and a cost model that calculated the costs to the population of each policy. They used this framework and data from Thailand to calculate the cost-effectiveness of six childhood vaccination policies in Thailand (one with TIV and five with LAIV that targeted children of different ages) against a baseline policy of 10% TIV coverage in the elderly; they also investigated the cost-effectiveness of increasing vaccination in the elderly to 66%. All seven vaccination policies tested reduced influenza cases and deaths compared to the baseline policy, but the LAIV-based polices were consistently better than the TIV-based policies; the smallest reductions were seen when TIV coverage in elderly people was increased to 66%. All seven policies were highly cost-effective according to the World Health Organization’s threshold for cost-effectiveness. That is, the cost per DALY averted by each policy compared to the baseline policy (the incremental cost-effectiveness ratio) was less than Thailand’s gross domestic product per capita (the total economic output of a country divided by the number of people in the country).
What Do These Findings Mean?
These findings suggest that seasonal influenza vaccination of children with LAIV is likely to represent good value for money in Thailand and, potentially, in other middle- and low-income countries in the short term. The long-term consequences of annual influenza vaccination of children in Thailand cannot be reliably predicted, however, because of limitations in our current understanding of influenza immunity in populations. Moreover, the accuracy of these findings is limited by the assumptions built into the modeling framework, including the vaccine costs and efficacy that were used to run the model, which were estimated from limited data. Importantly, however, these findings support proposals for large-scale community-based controlled trials of policies to vaccinate children against influenza in low- and middle-income countries. Indeed, based on these findings, Thailand is planning to evaluate school-based seasonal influenza vaccination in a few provinces in 2016 before considering a nationwide program of seasonal influenza vaccination of children.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001829.
The UK National Health Service Choices website provides information for patients about seasonal influenza, about influenza vaccination, and about influenza vaccination in children
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza vaccines
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination, about children, influenza, and vaccination, and about herd immunity; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
The Thai National Influenza Center monitors influenza activity throughout Thailand
doi:10.1371/journal.pmed.1001829
PMCID: PMC4444096  PMID: 26011712
7.  Preliminary Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus 
Arthritis care & research  2011;63(9):1213-1223.
Objectives
To develop widely acceptable preliminary criteria of global flare for childhood-onset SLE (cSLE).
Methods
Pediatric rheumatologists (n=138) rated a total of 358 unique patient profiles (PP) with information about the cSLE flare descriptors (cSLE-FD) from two consecutive visits: patient global assessment of well-being, physician global assessment of disease activity (MD-global), health-related quality of life, anti-dsDNA antibodies, disease activity index score, protein/creatinine (P/C) ratio, complement levels and ESR. Based on 2996 rater responses about the course of cSLE (baseline vs. follow-up) the accuracy (sensitivity, specificity, area under the receiver operating characteristic curve) of candidate flare criteria was assessed. An international consensus conference was held to rank these candidate flare criteria as per the ACR-recommendations for the development and validation of criteria sets.
Results
The highest ranked candidate criteria considered absolute changes (Δ) of the SLEDAI or BILAG, MD-global, P/C ratio, and ESR; Flare scores can be calculated [0.5 × ΔSLEDAI + 0.45 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR], where values ≥ 1.04 are reflective of a flare. Similarly, BILAG-based flare scores [0.4 × ΔBILAG + 0.65 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR] of ≥ 1.15 were diagnostic of a flare. Flare scores increase with flare severity.
Conclusions
Consensus has been reached on preliminary criteria for global flares in cSLE. Further validation studies are needed to confirm the usefulness of the cSLE flare criteria in research and for clinical care.
doi:10.1002/acr.20507
PMCID: PMC3167979  PMID: 21618452
lupus; childhood-onset SLE; SLE; pediatric SLE; juvenile SLE; flare; criteria; children; cSLE
8.  Broad Blockade Antibody Responses in Human Volunteers after Immunization with a Multivalent Norovirus VLP Candidate Vaccine: Immunological Analyses from a Phase I Clinical Trial 
PLoS Medicine  2015;12(3):e1001807.
Background
Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers.
Methods and Findings
Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated.
Conclusions
Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations.
Trial Registration
ClinicalTrials.gov NCT01168401
Lisa Lindesmith and colleagues assess the potential of a candidate virus-like particle (VLP) vaccine to induce antibody responses to antigenically divergent norovirus strains.
Editors' Summary
Background
Worldwide, noroviruses cause one in five cases of viral gastroenteritis (often called stomach flu or winter vomiting disease), the symptoms of which include nausea, vomiting, and diarrhea. There is no specific treatment for infection with these highly contagious viruses, and no established approach to vaccine development. While most people recover from the symptoms of norovirus infection within a few days, young children and the elderly may become severely ill or die. An estimated annual 300 million cases of norovirus infection contribute to roughly 260,000 deaths, mostly among this vulnerable demographic and mostly in low-income countries. Like influenza viruses, many noroviruses are evolving via a process known as antigenic drift. Antigens are components of infectious agents (including viruses) that are recognized by antibodies, proteins that bind to and neutralize foreign invaders. Over time, noroviruses develop small changes in their antigens that allow them to escape from antibodies produced in response to earlier infections. Every two to four years, because of accumulated antigenic drift, a new strain of norovirus emerges to which the human population has no direct antibody immunity, and an outbreak occurs. Because vaccines usually contain a component of the infectious agent that stimulates immunity, antigenic drift complicates the process of vaccine development. To be worth the cost and effort, a norovirus vaccine must confer immunity against a diverse range of norovirus strains, ideally including strains beyond those represented within the vaccine itself.
Partly because there is not a reliable method for growing noroviruses in the laboratory, recent efforts have focused on developing candidate vaccines using virus-like particles (VLPs). VLPs are constructed from laboratory-generated molecules of the virus’s capsid (outer shell). These capsid proteins self-assemble into icosahedral VLPs, which resemble the viral shell. VLPs cannot infect people or cause illness, but because they contain viral antigens, they can induce the immune system to produce antibodies that may neutralize actual viruses. VLPs can also be used to study the antibodies that people produce in response to vaccination or infection.
Why Was This Study Done?
VLP-based vaccines are relatively new, and their capacity to elicit a broad immune response conferring protection to an evolving range of norovirus strains is not established. One VLP vaccine based on a single strain that circulates primarily in children conferred immunity to that strain. Another, multivalent (containing a mix of VLPs from more than one strain) VLP vaccine elicited antibody generation, but in a phase I clinical trial did not confer immunity to infection by a strain that had previously circulated globally. In the current study, the researchers explored two key questions using laboratory analysis of blood samples drawn from participants in that trial. First, they tested whether the vaccine elicits antibody responses to a broad range of norovirus strains, as antibody responses can provide clues to the potential for this type of vaccine to confer broad immunity in the future. Second, they investigated how preexisting exposure to noroviruses affects the immune system’s response to a vaccine—strategic information that could aid in future vaccine development.
What Did the Researchers Do and Find?
The researchers tested serum (blood without cells or clotting proteins; serum contains the antibodies generated by the immune system) collected from ten participants receiving one injection of the VLP vaccine followed by a second injection 28 days later. They analyzed the serum specimens for antibodies to vaccine VLPs and also to VLPs representing viruses that were not contained in the vaccine. They used two methods, both utilizing VLPs generated from 11 norovirus strains: a traditional method that assesses binding of serum antibodies to each of these VLPs, and a more recent method that assays the ability of antibodies to block the interaction of each VLP with a molecule on intestinal cells that binds to the virus (the gut epithelial ligand), enabling norovirus to enter and infect cells. Prior studies suggest that this latter assay may be a better proxy for actual immunity.
The researchers’ major finding is that a multivalent VLP vaccine (two VLPs representing four strains of norovirus: one from a subgroup called genotype GI.1 and another consensus VLP of three strains from the subgroup GII.4) can rapidly elicit serum antibodies that bind a range of vaccine and non-vaccine VLPs, and that block binding of these VLPs to the gut epithelial ligand. Notably, vaccine recipients also generated antibodies reactive to two novel VLPs representing human noroviruses that they could not have previously encountered, indicating that prior exposure to each norovirus strain was not required for the full antibody response following vaccination. However, based on an analysis of which specific epitopes (small regions on an antigen) the population of antibodies binds, the authors report that antibody responses to the vaccine prominently target epitopes of a 1997 strain of human GII.4 norovirus, and propose that exposure history does influence the antibody response.
What Do these Findings Mean?
These findings raise the possibility that the VLP vaccine may induce immunity not only to norovirus strains that have caused past outbreaks, but also to variants that have yet to enter the population—a necessary attribute given the antigenic drift observed among noroviruses. The study also indicates that VLP-induced antibody responses to norovirus are consistent with the “antigenic seniority” model, in which strains to which an individual was previously exposed influence the binding properties of a vaccine-induced antibody population. This latter finding may influence the design of future norovirus vaccines.
These results must be interpreted cautiously, particularly as they pertain to the potential for a norovirus vaccine to protect against natural infection. The study is small, and antibody binding and blocking assays may not replicate how the immune system of a vaccine recipient will respond to true norovirus infection. Additionally, the study participants were all adults aged 18 to 49 years, while a vaccine is most needed for young children (who account for the majority of severe infections) and the elderly (who are most likely to die from infection). Unlike the study participants, young children lack preexisting antibodies to norovirus. Older people are more likely to have been previously exposed to norovirus, but may show attenuated immune responses to vaccination. Adapting to the different immune responses of these two groups remains a central challenge to norovirus vaccine development.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001807.
The World Health Organization provides a comprehensive description of the disease burden from diarrheal disease
The MedlinePlus encyclopedia has a page on viral gastroenteritis (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on disease trends and outbreaks
The US Department of Health and Human Services offers guidance for prevention based on food safety
A 2014 interview with Academic Editor Benjamin Lopman explores the difficulty of developing a norovirus vaccine
The authors have previously published findings on the evolution of norovirus strains in PLOS Medicine and have discussed the challenges of norovirus therapeutic design in PLOS Pathogens
doi:10.1371/journal.pmed.1001807
PMCID: PMC4371888  PMID: 25803642
9.  Serum tenascin-C discriminates patients with active SLE from inactive patients and healthy controls and predicts the need to escalate immunosuppressive therapy: a cohort study 
Introduction
The aim of this study was to examine whether circulating levels of the proinflammatory glycoprotein tenascin-C (TNC) are useful as an activity-specific or predictive biomarker in systemic lupus erythematosus (SLE).
Methods
Serum TNC levels were determined by enzyme-linked immunosorbent assay at inception visit in a prospective cohort of 59 SLE patients, and in 65 healthy controls (HC). SLE patients were followed for a mean of 11 months, disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) and British Isles Lupus Assessment Group disease activity index (BILAG-2004), clinical and laboratory data were recorded every 3–6 months, and changes in glucocorticoids (GC) and immunosuppressants (IS) were recorded serially. We examined cross-sectionally the relationships between serum concentrations of TNC and SLE status, SLEDAI-2 K scores, strata of disease activity, and levels of conventional biomarkers [anti–double-stranded DNA (dsDNA), anti-nucleosome antibodies, C3 and C4]. We also explored the utility of TNC levels for predicting disease flares, defined as (i) new/increased GC, (ii) new/increased GC or IS, and (iii) increase in SLEDAI by ≥3 or (iv) BILAG A or B flare.
Results
There was no significant difference in the mean levels of TNC between the SLE patients and HC. However, in SLE patients with active disease (SLEDAI ≥6), the TNC levels were significantly higher than in the HC (p = 0.004) or in patients with no/low disease activity (p = 0.004). In SLE patients, TNC levels were significantly associated with positivity of anti-dsDNA (p = 0.03) and anti-nucleosome antibodies (p = 0.008). Flares defined by a need to escalate immunosuppressive therapy were captured more frequently and earlier than flares defined by standard activity indices. Higher baseline levels of serum TNC presented a significantly greater risk of flare (i) [hazard ratio (HR) 1.39, 95 % confidence interval (CI) 1.11–1.73] or (ii) (HR 1.25, 95 % CI 1.02–1.52) but not of flares (iii) or (iv). The baseline serum TNC level was the single most important independent predictor of flare (i) compared with conventional biomarkers.
Conclusions
TNC is not disease-specific, but it seems to indicate the activity of SLE and may predict the need to escalate immunosuppressive therapy. TNC levels may thus serve as a useful activity-specific and predictive biomarker in SLE.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0862-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0862-4
PMCID: PMC4660660  PMID: 26608564
Tenascin-C; Biomarker; SLE; Disease activity; Flare
10.  The Effects of Influenza Vaccination of Health Care Workers in Nursing Homes: Insights from a Mathematical Model 
PLoS Medicine  2008;5(10):e200.
Background
Annual influenza vaccination of institutional health care workers (HCWs) is advised in most Western countries, but adherence to this recommendation is generally low. Although protective effects of this intervention for nursing home patients have been demonstrated in some clinical trials, the exact relationship between increased vaccine uptake among HCWs and protection of patients remains unknown owing to variations between study designs, settings, intensity of influenza seasons, and failure to control all effect modifiers. Therefore, we use a mathematical model to estimate the effects of HCW vaccination in different scenarios and to identify a herd immunity threshold in a nursing home department.
Methods and Findings
We use a stochastic individual-based model with discrete time intervals to simulate influenza virus transmission in a 30-bed long-term care nursing home department. We simulate different levels of HCW vaccine uptake and study the effect on influenza virus attack rates among patients for different institutional and seasonal scenarios. Our model reveals a robust linear relationship between the number of HCWs vaccinated and the expected number of influenza virus infections among patients. In a realistic scenario, approximately 60% of influenza virus infections among patients can be prevented when the HCW vaccination rate increases from 0 to 1. A threshold for herd immunity is not detected. Due to stochastic variations, the differences in patient attack rates between departments are high and large outbreaks can occur for every level of HCW vaccine uptake.
Conclusions
The absence of herd immunity in nursing homes implies that vaccination of every additional HCW protects an additional fraction of patients. Because of large stochastic variations, results of small-sized clinical trials on the effects of HCW vaccination should be interpreted with great care. Moreover, the large variations in attack rates should be taken into account when designing future studies.
Using a mathematical model to simulate influenza transmission in nursing homes, Carline van den Dool and colleagues find that each additional staff member vaccinated further reduces the risk to patients.
Editors' Summary
Background.
Every winter, millions of people catch influenza, a contagious viral disease of the nose, throat, and airways. Most people recover completely from influenza within a week or two but some develop life-threatening complications such as bacterial pneumonia. As a result, influenza outbreaks kill about half a million people—mainly infants, elderly people, and chronically ill individuals—each year. To minimize influenza-related deaths, the World Health Organization recommends that vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins (antigens) that the immune system recognizes. This means that an immune response produced one year provides only partial protection against influenza the next year. To provide maximum protection against influenza, each year's vaccine contains disabled versions of the major circulating strains of influenza viruses.
Why Was This Study Done?
Most Western countries also recommend annual flu vaccination for health care workers (HCWs) in hospitals and other institutions to reduce the transmission of influenza to vulnerable patients. However, many HCWs don't get a regular flu shot, so should efforts be made to increase their rate of vaccine uptake? To answer this question, public-health experts need to know more about the relationship between vaccine uptake among HCWs and patient protection. In particular, they need to know whether a high rate of vaccine uptake by HCWs will provide “herd immunity.” Herd immunity occurs because, when a sufficient fraction of a population is immune to a disease that passes from person to person, infected people rarely come into contact with susceptible people, which means that both vaccinated and unvaccinated people are protected from the disease. In this study, the researchers develop a mathematical model to investigate the relationship between vaccine uptake among HCWs and patient protection in a nursing home department.
What Did the Researchers Do and Find?
To predict influenza virus attack rates (the number of patient infections divided by the number of patients in a nursing home department during an influenza season) at different levels of HCW vaccine uptake, the researchers develop a stochastic transmission model to simulate epidemics on a computer. This model predicts that as the HCW vaccination rate increases from 0 (no HCWs vaccinated) to 1 (all the HCWs vaccinated), the expected average influenza virus attack rate decreases at a constant rate. In the researchers' baseline scenario—a nursing home department with 30 beds where patients come into contact with other patients, HCWs, and visitors—the model predicts that about 60% of the patients who would have been infected if no HCWs had been vaccinated are protected when all the HCWs are vaccinated, and that seven HCWs would have to be vaccinated to protect one patient. This last figure does not change with increasing vaccine uptake, which indicates that there is no level of HCW vaccination that completely stops the spread of influenza among the patients; that is, there is no herd immunity. Finally, the researchers show that large influenza outbreaks can happen by chance at every level of HCW vaccine uptake.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these predictions may depend on the specific assumptions built into the model. Therefore the researchers verified that their findings hold for a wide range of plausible assumptions. These findings have two important practical implications. First, the direct relationship between HCW vaccination and patient protection and the lack of any herd immunity suggest that any increase in HCW vaccine uptake will be beneficial to patients in nursing homes. That is, increasing the HCW vaccination rate from 80% to 90% is likely to be as important as increasing it from 10% to 20%. Second, even 100% HCW vaccination cannot guarantee that influenza outbreaks will not occasionally occur in nursing homes. Because of the large variation in attack rates, the results of small clinical trials on the effects of HCW vaccination may be inaccurate and future studies will need to be very large if they are to provide reliable estimates of the amount of protection that HCW vaccination provides to vulnerable patients.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050200.
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Jeffrey Kwong and colleagues is also available
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
The UK Health Protection Agency also provides information on influenza
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about herd immunity, including a simple explanatory animation
The European Centre for Disease Prevention and Control provides an overview on the types of influenza
doi:10.1371/journal.pmed.0050200
PMCID: PMC2573905  PMID: 18959470
11.  Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study 
PLoS Medicine  2011;8(1):e1000388.
Results from a European multicentre case-control study reported by Marta Valenciano and colleagues suggest good protection by the pandemic monovalent H1N1 vaccine against pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine on H1N1.
Background
A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1).
Methods and Findings
Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9).
Conclusions
Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Following the World Health Organization's declaration of pandemic phase six in June 2009, manufacturers developed vaccines against pandemic influenza A 2009 (pH1N1). On the basis of the scientific opinion of the European Medicines Agency, the European Commission initially granted marketing authorization to three pandemic vaccines for use in European countries. During the autumn of 2009, most European countries included the 2009–2010 seasonal influenza vaccine and the pandemic vaccine in their influenza vaccination programs.
The Influenza Monitoring Vaccine Effectiveness in Europe network (established to monitor seasonal and pandemic influenza vaccine effectiveness) conducted seven case-control and three cohort studies in seven European countries in 2009–2010 to estimate the effectiveness of the pandemic and seasonal vaccines. Data from the seven pilot case-control studies were pooled to provide overall adjusted estimates of vaccine effectiveness.
Why Was This Study Done?
After seasonal and pandemic vaccines are made available to populations, it is necessary to estimate the effectiveness of the vaccines at the population level during every influenza season. Therefore, this study was conducted in European countries to estimate the pandemic influenza vaccine effectiveness and seasonal influenza vaccine effectiveness against people presenting to their doctor with influenza-like illness who were confirmed (by laboratory tests) to be infected with pH1N1.
What Did the Researchers Do and Find?
The researchers conducted a multicenter case-control study on the basis of practitioner surveillance networks from seven countries—France, Hungary, Ireland, Italy, Romania, Portugal, and Spain. Patients consulting a participating practitioner for influenza-like illness had a nasal or throat swab taken within 8 days of symptom onset. Cases were swabbed patients who tested positive for pH1N1. Patients presenting with influenza-like illness whose swab tested negative for any influenza virus were controls.
Individuals were considered vaccinated if they had received a dose of the vaccine more than 14 days before the date of onset of influenza-like illness and unvaccinated if they were not vaccinated at all, or if the vaccine was given less than 15 days before the onset of symptoms. The researchers analyzed pandemic influenza vaccination effectiveness in those vaccinated less than 8 days, those vaccinated between and including 8 and 14 days, and those vaccinated more than 14 days before onset of symptoms compared to those who had never been vaccinated.
The researchers used modeling (taking account of all potential confounding factors) to estimate adjusted vaccine effectiveness and stratified the adjusted pandemic influenza vaccine effectiveness and the adjusted seasonal influenza vaccine effectiveness in three age groups (<15, 15–64, and ≥65 years of age).
The adjusted results suggest that the 2009–2010 seasonal influenza vaccine did not protect against pH1N1 illness. However, one dose of the pandemic vaccines used in the participating countries conferred good protection (65.5%–100% according to various stratifications performed) against pH1N1 in people who attended their practitioner with influenza-like illness, especially in people aged <65 years and in those without any chronic disease. Furthermore, good pandemic influenza vaccine effectiveness was observed as early as 8 days after vaccination.
What Do These Findings Mean?
The results of this study provide early estimates of the pandemic influenza vaccine effectiveness suggesting that the monovalent pandemic vaccines have been effective. The findings also give an indication of the vaccine effectiveness for the Influenza A (H1N1) 2009 strain included in the 2010–2011 seasonal vaccines, although specific vaccine effectiveness studies will have to be conducted to verify if similar good effectiveness are observed with 2010–2011 trivalent vaccines. However, the results of this study should be interpreted with caution because of limitations in the pandemic context (late timing of the studies, low incidence, low vaccine coverage leading to imprecise estimates) and potential biases due the study design, confounding factors, and missing values. The researchers recommend that in future season studies, the sample size per country should be enlarged in order to allow for precise pooled and stratified analyses.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000388.
The World Health Organization has information on H1N1 vaccination
The US Centers for Disease Control and Prevention provides a fact sheet on the 2009 H1N1 influenza virus
The US Department of Health and Human services has a comprehensive website on flu
The European Centre for Disease Prevention and Control provides information on 2009 H1N1 pandemic
The European Centre for Disease Prevention and Control presents a summary of the 2009 H1N1 pandemic in Europe and elsewhere
doi:10.1371/journal.pmed.1000388
PMCID: PMC3019108  PMID: 21379316
12.  Herpes Zoster Vaccination in SLE: A pilot study of Immunogenicity 
The Journal of rheumatology  2013;40(11):10.3899/jrheum.130170.
Background
Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been FDA approved, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of Zostavax® in SLE patients.
Methods
Ten SLE patients and 10 controls ≥50 years old participated in this open label vaccination study. All were seropositive for varicella zoster virus (VZV). SLE patients were excluded for SLEDAI>4, use of mycophenolatemofetil, cyclophosphamide, biologics, or >10 mg prednisone daily. Follow-up visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific IFN-γ producing ELISPOT assays and with antibody concentrations.
Results
All subjects were women. SLE patients were slightly older than controls (60.5 vs. 55.3 years, p<0.05) Median baseline SLEDAI was 0 (range 0–2) for SLE patients. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a >50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p<0.05).
Conclusions
Zostavax vaccination yielded a measurable immuneresponse in this cohort of mild SLE patients on mild-moderate immunosuppressive medications. No herpetiform lesions or lupus flares were seen in this small cohort of patients.
doi:10.3899/jrheum.130170
PMCID: PMC3867792  PMID: 24037550
Systemic lupus erythematosus; herpes zoster; vaccine; Zostavax; infection; clinical trial
13.  Assessing Optimal Target Populations for Influenza Vaccination Programmes: An Evidence Synthesis and Modelling Study 
PLoS Medicine  2013;10(10):e1001527.
Marc Baguelin and colleagues use virological, clinical, epidemiological, and behavioral data to estimate how policies for influenza vaccination programs may be optimized in England and Wales.
Please see later in the article for the Editors' Summary
Background
Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality.
Methods and Findings
Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34–0.45) infections per dose of vaccine and 1.74 (1.16–3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5–16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52–0.81) infections per dose and 1.95 (1.28–3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50–64-y-olds) would prevent only 0.43 (0.35–0.52) infections per dose and 1.77 (1.15–3.14) deaths per 1,000 doses.
Conclusions
This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza, a viral infection of the airways. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) kill about half a million people annually. In countries with advanced health systems, these deaths occur mainly among elderly people and among individuals with long-term illnesses such as asthma and heart disease that increase the risk of complications occurring after influenza virus infection. Epidemics of influenza occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection provides only partial protection against influenza the following year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza by preparing the immune system to respond quickly when challenged by a live influenza virus. Consequently, many countries run seasonal influenza vaccination programs that, in line with World Health Organization recommendations, target individuals 65 years old and older and people in high-risk groups.
Why Was This Study Done?
Is this approach the best use of available resources? Might, for example, vaccination of children—the main transmitters of influenza—provide more benefit to the whole population than vaccination of elderly people? Vaccination of children would not directly prevent as many influenza-related deaths as vaccination of elderly people, but it might indirectly prevent deaths in elderly adults by inducing herd immunity—vaccination of a large part of a population can protect unvaccinated members of the population by reducing the chances of an infection spreading. Policy makers need to know whether a change to an influenza vaccination program is likely to provide additional population benefits before altering the program. In this evidence synthesis and modeling study, the researchers combine (synthesize) longitudinal influenza surveillance datasets (data collected over time) from England and Wales, develop a mathematical model for influenza transmission based on these data using a Bayesian statistical approach, and use the model to evaluate the impact on influenza infections and deaths of changes to the seasonal influenza vaccination program in England and Wales.
What Did the Researchers Do and Find?
The researchers developed an influenza transmission model using clinical data on influenza-like illness consultations collected in a primary care surveillance scheme for each week of 14 influenza seasons in England and Wales, virological information on respiratory viruses detected in a subset of patients presenting with clinically suspected influenza, and data on vaccination coverage in the whole population (epidemiological data). They also incorporated data on social contacts (behavioral data) and on immunity to influenza viruses in the population (seroepidemiological data) into their model. To estimate the impact of potential changes to the current vaccination strategy in England and Wales, the researchers used their model, which replicated the patterns of disease observed in the surveillance data, to run simulated epidemics for each influenza season and for three strains of influenza virus under various vaccination scenarios. Compared to no vaccination, the current program (vaccination of people 65 years old and older and people in high-risk groups) averted 0.39 infections per dose of vaccine and 1.74 deaths per 1,000 doses. Notably, the model predicted that extension of the program to target 5–16-year-old children would increase the efficiency of the program and would avert 0.70 infections per dose and 1.95 deaths per 1,000 doses.
What Do These Findings Mean?
The finding that the transmission model developed by the researchers closely fit the available surveillance data suggests that the model should be able to predict what would have happened in England and Wales over the study period if an alternative vaccination regimen had been in place. The accuracy of such predictions may be limited, however, because the vaccination model is based on a series of simplifying assumptions. Importantly, given that influenza vaccination for children is being rolled out in England and Wales from September 2013, the model confirms that children are key spreaders of influenza and suggests that a vaccination program targeting children will reduce influenza infections and potentially influenza deaths in the whole population. More generally, the findings of this study support wider adoption of national vaccination strategies designed to block influenza transmission and to target those individuals most at risk from the complications of influenza infection.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371.journal.pmed.1001527.
The UK National Health Service Choices website provides information for patients about seasonal influenza and about vaccination; Public Health England (formerly the Health Protection Agency) provides information on influenza surveillance in the UK, including information about the primary care surveillance database used in this study
The World Health Organization provides information on seasonal influenza (in several languages)
The European Influenzanet is a system to monitor the activity of influenza-like illness with the aid of volunteers via the Internet
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination and about the US influenza surveillance system; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001527
PMCID: PMC3793005  PMID: 24115913
14.  Cross-Reactive Neuraminidase Antibodies Afford Partial Protection against H5N1 in Mice and Are Present in Unexposed Humans 
PLoS Medicine  2007;4(2):e59.
Background
A pandemic H5N1 influenza outbreak would be facilitated by an absence of immunity to the avian-derived virus in the human population. Although this condition is likely in regard to hemagglutinin-mediated immunity, the neuraminidase (NA) of H5N1 viruses (avN1) and of endemic human H1N1 viruses (huN1) are classified in the same serotype. We hypothesized that an immune response to huN1 could mediate cross-protection against H5N1 influenza virus infection.
Methods and Findings
Mice were immunized against the NA of a contemporary human H1N1 strain by DNA vaccination. They were challenged with recombinant A/Puerto Rico/8/34 (PR8) viruses bearing huN1 (PR8-huN1) or avN1 (PR8-avN1) or with H5N1 virus A/Vietnam/1203/04. Additional naïve mice were injected with sera from vaccinated mice prior to H5N1 challenge. Also, serum specimens from humans were analyzed for reactivity with avN1. Immunization elicited a serum IgG response to huN1 and robust protection against the homologous challenge virus. Immunized mice were partially protected from lethal challenge with H5N1 virus or recombinant PR8-avN1. Sera transferred from immunized mice to naïve animals conferred similar protection against H5N1 mortality. Analysis of human sera showed that antibodies able to inhibit the sialidase activity of avN1 exist in some individuals.
Conclusions
These data reveal that humoral immunity elicited by huN1 can partially protect against H5N1 infection in a mammalian host. Our results suggest that a portion of the human population could have some degree of resistance to H5N1 influenza, with the possibility that this could be induced or enhanced through immunization with seasonal influenza vaccines.
Humoral immunity against endemic human H1N1 influenza viruses can partially protect mice against H5N1 challenge, raising the possibility that a portion of the human population could have some degree of resistance against avian flu.
Editors' Summary
Background.
Every winter, millions of people catch influenza—a viral infection of the airways. Most recover quickly but influenza can kill infants, elderly people, and chronically ill individuals. To minimize these deaths, the World Health Organization recommends that vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins (antigens) that the immune system recognizes. Each year's vaccine contains disabled versions of the circulating strains of influenza A type H1N1 and H3N2 viruses, and of influenza B virus. The H and N refer to the major influenza A antigens (hemagglutinin and neuraminidase), and the numbers refer to the type of each antigen; different H1N1 and H3N2 virus strains contain small variations in their respective hemagglutinin and neuraminidase type. Vaccines provide protection against seasonal influenza outbreaks, but sometimes flu viruses emerge that contain major antigenic changes, such as a different hemagglutinin type. These viruses can start pandemics (global outbreaks) because populations have little immunity to them. Many scientists believe that avian (bird) H5N1 influenza virus (which has caused about 250 confirmed cases of human flu and 150 deaths) could trigger the next human pandemic.
Why Was This Study Done?
Avian influenza H5N1 virus has not started a human pandemic yet because it cannot move easily between people. If it acquires this property, it could kill millions before an effective vaccine could be developed, so researchers are looking for other ways to provide protection against avian H5N1. One possibility is that an immune response to the human type 1 neuraminidase (huN1) in circulating H1N1 influenza virus strains and vaccines could provide some protection against avian H5N1 influenza virus, which contains the closely related avian type 1 neuraminidase (avN1). In this study, the researchers have investigated this possibility in mice and in a small human study.
What Did the Researchers Do and Find?
The researchers immunized mice with DNA encoding the huN1 present in a circulating H1N1 virus. They then examined the immune response of the mice to this huN1 and to avN1 from an avian H5N1 virus isolated from a human patient (A/Vietnam/1203/04). Most of the mice made antibodies (proteins that recognize antigens) against huN1; a few also made detectable levels of antibodies against avN1. All the vaccinated mice survived infection with a man-made flu virus containing huN1, and half also survived infection with low doses of a man-made virus containing avN1 or A/Vietnam/1203/04. To test whether the antibodies made by the vaccinated mice were responsible for this partial protection, the researchers collected serum (the liquid part of blood that contains the antibodies) from them and injected it into unvaccinated mice. Again, about half of the mice survived infection with the H5N1 virus, which indicates that the huN1-induced immunity against H5N1 is largely mediated by antibodies. Finally, the researchers tested serum samples from 38 human volunteers for their ability to inhibit neuraminidase from an H1N1 virus and two H5N1 viruses (antibodies to neuraminidase reduce viral replication and disease severity by inhibiting neuraminidase activity). Most of the sera inhibited the enzyme from the H1N1 virus; and seven also inhibited the enzyme from both H5N1 viruses.
What Do These Findings Mean?
These findings indicate that a vaccine containing huN1 induces the production of antibodies in mice that partly protect them against H5N1 infection. In addition, the human study suggests that some people may have some degree of resistance to H5N1 influenza because of exposure to H1N1 viruses or routine influenza vaccination. These results, while intriguing, don't show that there is actual protection, but it seems well worth doing additional work to address this question. The researchers also suggest that many more people might have been infected already with H5N1 but their strong H1N1 immunity meant they had only mild symptoms, and this hypothesis also deserves further investigation. Overall, these findings raise the possibility that seasonal influenza vaccination may provide some protection against pandemic H5N1. It is worth discussing whether, even while further studies are underway, seasonal vaccination should be increased, especially in areas where H5N1 is present in birds.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040059.
A related PLoS Medicine Perspective article by Laura Gillim-Ross and Kanta Subbarao is available
US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including key facts about avian influenza and vaccination
US National Institute of Allergy and Infectious Disease has a feature on seasonal, avian and pandemic flu
World Health Organization has fact sheets on influenza and influenza vaccines, and information on avian influenza
UK Health Protection Agency provides information on seasonal, avian, and pandemic influenza
doi:10.1371/journal.pmed.0040059
PMCID: PMC1796909  PMID: 17298168
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.  Global Role and Burden of Influenza in Pediatric Respiratory Hospitalizations, 1982–2012: A Systematic Analysis 
PLoS Medicine  2016;13(3):e1001977.
Background
The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide.
Methods and Findings
We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5–17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status.
Influenza was associated with 10% (95% CI 8%–11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%–7%) among children <6 mo to 16% (95% CI 14%–20%) among children 5–17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y—of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo—and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings.
Conclusions
Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.
The substantial global burden of influenza infections in children is revealed by Lafond and colleagues. Children in developing countries are 3 times more likely to be hospitalised and treatments vary. This study highlights the need for vaccination programs in the young.
Editors' Summary
Background
Acute lower respiratory infections—bacterial and viral infections of the lungs and airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for 15% of deaths among children under five years old and kills nearly one million young children every year. Globally, infections with respiratory syncytial virus and with Streptococcus pneumoniae are associated with about 25% and 18.3%, respectively, of all episodes of severe respiratory infection in young children. Another infectious organism that contributes to the global burden of respiratory disease among children is the influenza virus. Every year, millions of people become infected with this virus, which infects the airways and causes symptoms that include a high temperature, tiredness and weakness, general aches and pains, and a dry chesty cough. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) nevertheless kill about half a million people annually, with the highest burden of severe disease being experienced by elderly people and by children under five years old.
Why Was This Study Done?
Annual immunization (vaccination) can reduce an individual’s risk of catching influenza, but before a country implements this preventative measure, policymakers need reliable estimates of the burden of influenza in their country. Although such estimates have been calculated for resource-rich countries with temperate climates, where influenza largely occurs in the winter, few estimates of influenza burden are available for resource-limited countries, which has hampered informed consideration of vaccination for influenza prevention in many settings. Recently, however, there has been a global expansion of systematic surveillance and testing for influenza virus among patients admitted to hospital for severe respiratory infection. Here, the researchers use this expanded surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide between 1982 and 2012. Specifically, they undertake a systematic review to identify published research articles on influenza-associated respiratory disease in hospitalized children, and, by aggregating the data from these articles with data collected by hospital-based influenza surveillance, they calculate a pooled estimate of the proportion of children hospitalized with respiratory disease who are positive for influenza.
What Did the Researchers Do and Find?
Using predefined search criteria, the researchers identified 108 published research articles that provided information on influenza-associated respiratory illness among hospitalized children. In addition, the Global Respiratory Hospitalizations–Influenza Proportion Positive (GRIPP) working group provided 37 hospital-based influenza surveillance datasets. By aggregating the data from these sources using a statistical approach called meta-analysis, the researchers calculated that, overall, influenza was associated with 9.5% of hospitalizations for severe respiratory infection among children under 18 years old worldwide, ranging from 4.8% among children under six months old to 16.4% among children aged 5–17 years. The researchers also calculated that, on average over the study period, influenza resulted in about 374,000 hospitalizations annually among children under one year old (including 228,000 hospitalizations among children less than six months old) and nearly one million hospitalizations annually among children under five years old. Finally, the researchers calculated that influenza-associated hospitalization rates among children under five years old over the study period were more than three times higher in resource-limited countries than in industrialized countries (150 and 48 hospitalizations, respectively, per 100,000 children per year).
What Do These Findings Mean?
Differences in hospitalization practices, in applications of case definitions, and in influenza testing protocols between settings may affect the accuracy of these findings. Specifically, the approach taken by the researchers may mean that their estimate of the total burden of severe respiratory disease due to influenza is an underestimate of the true situation. Even so, these findings suggest that influenza is an important contributor to hospitalizations for severe respiratory illness among children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could, therefore, reduce the contribution that influenza makes to hospitalizations for respiratory infections among children. Importantly, the estimates of the burden of influenza provided by these findings can now be used by countries considering influenza vaccination programs for children and/or pregnant women to help them investigate the possible health and cost implications of such programs and should also stimulate further research into the development of effective influenza vaccines for young children.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001977.
The UK National Health Service Choices website provides information about respiratory infections, seasonal influenza, influenza vaccination, and influenza vaccination in children
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza vaccines
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects seasonal influenza, including information about vaccination, and about children, influenza, and vaccination; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
doi:10.1371/journal.pmed.1001977
PMCID: PMC4807087  PMID: 27011229
17.  Impact of standard of care treatments and disease variables on outcomes in systemic lupus erythematosus trials: analysis from the Lupus Foundation of America Collective Data Analysis Initiative 
Objective
Most clinical trials for systemic lupus erythematosus (SLE) study the efficacy and safety of investigational agents added to variable background immunosuppressants, which has resulted in high response rates in patients treated with placebo plus standard of care (SOC) plus rescue measures. This project compared the impact of different SOC treatments and disease variables on the outcomes of SLE trials.
Material and Methods
Data were obtained from 981 patients receiving only SOC treatments in three nephritis and three general SLE trials to compare response and flare rates on the basis of the British Isles Lupus Assessment Group (BILAG) index, a measure common to all trials.
Results
For subjects enrolled in general SLE trials (n=173), those receiving mycophenolate mofetil (MMF) had more severe baseline disease, included more patients of African descent, and were administered higher baseline steroid doses compared with those receiving azathioprine (AZA) or methotrexate (MTX). BILAG responses at week 12 were MMF 35%, AZA 49%, MTX 34%, and no immunosuppressant (NIS) 65%. At week 52, MMF response rates increased to 41% despite reducing the steroid doses, but fell in all others (p=0.07, adjusted for steroids). Patients with severe disease activity at baseline (SDAB) who were defined as ≥1 BILAG A (severe) organ score had lower response rates to AZA or MTX but higher rates to MMF or NIS. Interim flares were highest with MMF [flares/patient–year (pt–yr)]. For all flares, rates were as follows: AZA 1.24, MMF 1.87, MTX 1.42, and NIS 0.81 and severe flares were as follows: AZA 0.66, MMF 1.29, MTX: 1.20, and NIS 0.55. Interim flares occurred in 71% of MMF-endpoint responders, 54% of AZA, 50% of MTX, and 22% of NIS. Patients with SDAB had more flares than moderate patients in the MMF and MTX groups: MMF: 2.39 vs. 1.03 flares/pt–yr (p=0.01), MTX: 2.33 vs. 0.63 (p=0.0002), severe flares: 1.87 vs. 0.34 for MMF (p=0.0013), 2.13 vs. 0.40 for MTX (p<0.0001). In nephritis trials (n=808), MMF subjects received less steroids than intravenous cyclophosphamide and response rates were similar, but MMF-treated patients had fewer severe flares (p=0.03).
Conclusion
Compared with MMF, AZA and MTX were associated with lower response rates at week 52. AZA-treated subjects had fewer flares and remained more stable in trials while engendering lower placebo plus SOC responses. MMF-treated subjects had frequent responses but more flares, suggesting that flares should be included in endpoint definitions. Given the likelihood of treatment selection bias, these data do not provide conclusions regarding efficacy but may help future trial designs by distinguishing factors definable at entry that are predictive of outcomes.
doi:10.5152/eurjrheum.2015.0048
PMCID: PMC5042268  PMID: 27708963
Systemic lupus; clinical trials; immunosuppressants
18.  B Lymphocyte Stimulator Levels in Systemic Lupus Erythematosus: Higher Circulating Levels in African American Patients and Increased Production after Influenza Vaccination in Patients with Low Baseline Levels 
Arthritis and rheumatism  2011;63(12):3931-3941.
Objective
Examine the relationship between circulating B lymphocyte stimulator (BLyS) levels and humoral responses to influenza vaccination in systemic lupus erythematosus (SLE) patients, as well as the effect of vaccination on BLyS levels. Clinical and serologic features of SLE that are associated with elevated BLyS levels will also be investigated.
Methods
Clinical history, disease activity measurements and blood specimens were collected from sixty SLE patients at baseline and after influenza vaccination. Sera were tested for BLyS levels, lupus-associated autoantibodies, serum IFN-α activity, 25-hydroxyvitamin D, and humoral responses to influenza vaccination.
Results
Thirty percent of SLE patients had elevated BLyS levels, with African American patients having higher BLyS levels than European American patients (p=0.006). Baseline BLyS levels in patients were not correlated with humoral responses to influenza vaccination (p=0.863), and BLyS levels increased post-vaccination only in the subset of patients in the lowest quartile of BLyS levels (p=0.0003). Elevated BLyS levels were associated with increased disease activity as measured by SLEDAI, PGA, and SLAM in European Americans (p=0.035, p=0.016, p=0.018, respectively), but not in African Americans. Elevated BLyS levels were also associated with anti-nRNP (p=0.0003) and decreased 25(OH)D (p=0.018). Serum IFN-α activity was a significant predictor of elevated BLyS in a multivariate analysis (p=0.002).
Conclusion
African American SLE patients have higher BLyS levels regardless of disease activity. Humoral response to influenza vaccination is not correlated with baseline BLyS levels in SLE patients and only those patients with low baseline BLyS levels demonstrate an increased BLyS response after vaccination.
doi:10.1002/art.30598
PMCID: PMC3234134  PMID: 22127709
Systemic lupus erythematosus (SLE); Cytokines
19.  Vaccinating to Protect a Vulnerable Subpopulation 
PLoS Medicine  2007;4(5):e174.
Background
Epidemic influenza causes serious mortality and morbidity in temperate countries each winter. Research suggests that schoolchildren are critical in the spread of influenza virus, while the elderly and the very young are most vulnerable to the disease. Under these conditions, it is unclear how best to focus prevention efforts in order to protect the population. Here we investigate the question of how to protect a population against a disease when one group is particularly effective at spreading disease and another group is more vulnerable to the effects of the disease.
Methods and Findings
We developed a simple mathematical model of an epidemic that includes assortative mixing between groups of hosts. We evaluate the impact of different vaccine allocation strategies across a wide range of parameter values. With this model we demonstrate that the optimal vaccination strategy is extremely sensitive to the assortativity of population mixing, as well as to the reproductive number of the disease in each group. Small differences in parameter values can change the best vaccination strategy from one focused on the most vulnerable individuals to one focused on the most transmissive individuals.
Conclusions
Given the limited amount of information about relevant parameters, we suggest that changes in vaccination strategy, while potentially promising, should be approached with caution. In particular, we find that, while switching vaccine to more active groups may protect vulnerable groups in many cases, switching too much vaccine, or switching vaccine under slightly different conditions, may lead to large increases in disease in the vulnerable group. This outcome is more likely when vaccine limitation is stringent, when mixing is highly structured, or when transmission levels are high.
Jonathan Dushoff and colleagues model the benefits of different vaccination strategies and suggest that small differences in how populations mix can change the best vaccination strategy from one focused on the most vulnerable individuals to one focused on the most transmissive individuals.
Editors' Summary
Background.
Every winter, millions of people take to their beds with influenza—a viral infection of the nose, throat, and airways that is transmitted in airborne droplets released by coughing and sneezing. Most people who catch flu recover within a few days, but some develop serious complications such as pneumonia, and in the US alone, about 36,000 people—mainly infants, elderly, and chronically ill individuals—die every year. To minimize the morbidity (illness) and mortality (death) associated with seasonal (epidemic) influenza, the World Health Organization recommends that these vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins that the immune system recognizes.
Why Was This Study Done?
Although infants and the elderly are particularly vulnerable to influenza, schoolchildren are more likely to spread the flu virus. Also, vaccination is more effective in schoolchildren than in elderly people. So could vaccination of schoolchildren be the best way to reduce influenza morbidity and mortality? Some Japanese and US data suggest that it might be, but policymakers need to know more about the likely effects of changing the current influenza vaccination strategy. They need to know in what circumstances the direct effects of vaccination (protection of vaccinated individuals from disease) outweigh its indirect effects (reduced infection in vulnerable individuals caused by the reduced spread of disease in the whole population) and when the opposite is true. In this study, the researchers have used mathematical modeling to investigate how vaccination affects the spread of diseases such as influenza for which a “core” group in the population spreads the disease and a distinct “vulnerable” group is sensitive to its effects.
What Did the Researchers Do and Find?
The researchers developed a mathematical model in which members of each group mixed mainly with their own group (assortative mixing) and used it to predict how changing the proportion of a limited amount of vaccine given to each group might affect disease spread under different conditions. For example, they report that in a population in which the two groups were very unlikely to mix and viral transmission was low, switching vaccine from the vulnerable group to the core group initially increased infections in the vulnerable group because fewer individuals were directly protected but, as more vaccine was allocated to the core group, fewer vulnerable people became infected because the size of the epidemic decreased. When viral transmission was high, vaccination of the vulnerable group was always best. However, when viral transmission was moderate, shifting vaccine from the vulnerable group first increased, then decreased infections in this group before increasing them again. This last change occurred when vaccination in the vulnerable group was so low that viral transmission was sufficient to maintain the epidemic within this group.
What Do These Findings Mean?
As with all mathematical modeling, the researchers' findings depend on the assumptions included in the model, many of which are based on limited information. The model also considers a population that contains only two groups, an unlikely situation in real life. Nevertheless, these findings indicate that in a population in which one group of people is mainly responsible for the spread of a disease and another is most vulnerable to its effects, the best vaccination strategy is very sensitive to how the groups mix and how well the disease spreads in each group. Small changes in these poorly understood parameters can change the optimal vaccination strategy from one that vaccinates vulnerable individuals to one that mainly vaccinates the people who spread the disease. Importantly, a beneficial change in strategy can become deleterious if taken too far, so policy makers need to approach potentially promising changes in vaccination policy cautiously. Finally, for influenza, the model supports the idea that using some vaccine stocks in schoolchildren might decrease morbidity and mortality among elderly people but suggests that—even if this turns out to be correct—if all the vaccine were given to schoolchildren, more old people might die. Thus, the most prudent policy would be to supplement rather than replace vaccination of the elderly with vaccination of children.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040174.
US Centers for Disease Control and Prevention provide information about influenza for patients and professionals, including key facts about the flu vaccine (in English and Spanish)
World Health Organization, fact sheet on influenza and information on vaccination (in English, Spanish, French, Arabic, Chinese and Russian)
UK Health Protection Agency, information on seasonal influenza
MedlinePlus encyclopedia entries on influenza and the influenza vaccine (in English and Spanish)
Public disease mortality and morbidity data at the International Infectious Disease Data Archive (IIDDA)
doi:10.1371/journal.pmed.0040174
PMCID: PMC1872043  PMID: 17518515
20.  Towards the Development of Criteria for Global Flares in Juvenile Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(6):811-820.
Objective
To develop a definition of global flare in jSLE and derive candidate criteria for measuring jSLE flares.
Methods
Pediatric rheumatologists answered two Delphi questionnaires to achieve consensus on a common definition of jSLE flare and identify variables for use in candidate flare criteria. The diagnostic accuracy of these candidate flare criteria was tested with data from jSLE patients (n=98; 623 visits total). Physician-rated change in the jSLE course (worsening yes/no) between visits served as the criterion standard.
Results
There was 96% consensus that a “a flare is a measurable worsening of jSLE disease activity in at least one organ system, involving new or worse signs of disease that may be accompanied by new or worse SLE symptoms. Depending on the severity of the flare, more intensive therapy may be required”. Variables suggested for use in flare criteria were: physician-rated disease activity (V1), patient well-being, protein:creatinine ratio, validated disease activity index (V2), Child Health Questionnaire physical summary score (V3), anti-dsDNA antibodies, ESR, and complement levels. Using multiple logistic regression, several candidate flare criteria were derived with area under the receiver operating characteristic curve (AUC) as high as 0.92 (sensitivity≥ 85%; specificity≥ 85%); CART analysis suggested that V1, V2 and V3 suffice to identify jSLE flares (AUC = 0.81; sensitivity = 64%; specificity = 86%).
Conclusions
Consensus about a definition of global disease flare with jSLE has been obtained and promising candidate flare criteria have been developed. These will need further assessment of their ease-of-use and accuracy in prospective study.
doi:10.1002/acr.20126
PMCID: PMC3049164  PMID: 20535792
jSLE; cSLE; children; flare criteria; flare; lupus
21.  Monitoring the Impact of Influenza by Age: Emergency Department Fever and Respiratory Complaint Surveillance in New York City 
PLoS Medicine  2007;4(8):e247.
Background
The importance of understanding age when estimating the impact of influenza on hospitalizations and deaths has been well described, yet existing surveillance systems have not made adequate use of age-specific data. Monitoring influenza-related morbidity using electronic health data may provide timely and detailed insight into the age-specific course, impact and epidemiology of seasonal drift and reassortment epidemic viruses. The purpose of this study was to evaluate the use of emergency department (ED) chief complaint data for measuring influenza-attributable morbidity by age and by predominant circulating virus.
Methods and Findings
We analyzed electronically reported ED fever and respiratory chief complaint and viral surveillance data in New York City (NYC) during the 2001–2002 through 2005–2006 influenza seasons, and inferred dominant circulating viruses from national surveillance reports. We estimated influenza-attributable impact as observed visits in excess of a model-predicted baseline during influenza periods, and epidemic timing by threshold and cross correlation. We found excess fever and respiratory ED visits occurred predominantly among school-aged children (8.5 excess ED visits per 1,000 children aged 5–17 y) with little or no impact on adults during the early-2002 B/Victoria-lineage epidemic; increased fever and respiratory ED visits among children younger than 5 y during respiratory syncytial virus-predominant periods preceding epidemic influenza; and excess ED visits across all ages during the 2003–2004 (9.2 excess visits per 1,000 population) and 2004–2005 (5.2 excess visits per 1,000 population) A/H3N2 Fujian-lineage epidemics, with the relative impact shifted within and between seasons from younger to older ages. During each influenza epidemic period in the study, ED visits were increased among school-aged children, and each epidemic peaked among school-aged children before other impacted age groups.
Conclusions
Influenza-related morbidity in NYC was highly age- and strain-specific. The impact of reemerging B/Victoria-lineage influenza was focused primarily on school-aged children born since the virus was last widespread in the US, while epidemic A/Fujian-lineage influenza affected all age groups, consistent with a novel antigenic variant. The correspondence between predominant circulating viruses and excess ED visits, hospitalizations, and deaths shows that excess fever and respiratory ED visits provide a reliable surrogate measure of incident influenza-attributable morbidity. The highly age-specific impact of influenza by subtype and strain suggests that greater age detail be incorporated into ongoing surveillance. Influenza morbidity surveillance using electronic data currently available in many jurisdictions can provide timely and representative information about the age-specific epidemiology of circulating influenza viruses.
Don Olson and colleagues report that influenza-related morbidity in NYC from 2001 to 2006 was highly age- and strain-specific and conclude that surveillance using electronic data can provide timely and representative information about the epidemiology of circulating influenza viruses.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza (a viral infection of the nose, throat, and airways) send millions of people to their beds every winter. Most recover quickly, but flu epidemics often disrupt daily life and can cause many deaths. Seasonal epidemics occur because influenza viruses continually make small changes to the viral proteins (antigens) that the human immune system recognizes. Consequently, an immune response that combats influenza one year may provide partial or no protection the following year. Occasionally, an influenza virus with large antigenic changes emerges that triggers an influenza pandemic, or global epidemic. To help prepare for both seasonal epidemics and pandemics, public-health officials monitor influenza-related illness and death, investigate unusual outbreaks of respiratory diseases, and characterize circulating strains of the influenza virus. While traditional influenza-related illness surveillance systems rely on relatively slow voluntary clinician reporting of cases with influenza-like illness symptoms, some jurisdictions have also started to use “syndromic” surveillance systems. These use electronic health-related data rather than clinical impression to track illness in the community. For example, increased visits to emergency departments for fever or respiratory (breathing) problems can provide an early warning of an influenza outbreak.
Why Was This Study Done?
Rapid illness surveillance systems have been shown to detect flu outbreaks earlier than is possible through monitoring deaths from pneumonia or influenza. Increases in visits to emergency departments by children for fever or respiratory problems can provide an even earlier indicator. Researchers have not previously examined in detail how fever and respiratory problems by age group correlate with the predominant circulating respiratory viruses. Knowing details like this would help public-health officials detect and respond to influenza epidemics and pandemics. In this study, the researchers have used data collected between 2001 and 2006 in New York City emergency departments to investigate these aspects of syndromic surveillance for influenza.
What Did the Researchers Do and Find?
The researchers analyzed emergency department visits categorized broadly into a fever and respiratory syndrome (which provides an estimate of the total visits attributable to influenza) or more narrowly into an influenza-like illness syndrome (which specifically indicates fever with cough and/or sore throat) with laboratory-confirmed influenza surveillance data. They found that emergency department visits were highest during peak influenza periods, and that the affect on different age groups varied depending on the predominant circulating viruses. In early 2002, an epidemic reemergence of B/Victoria-lineage influenza viruses caused increased visits among school-aged children, while adult visits did not increase. By contrast, during the 2003–2004 season, when the predominant virus was an A/H3N2 Fujian-lineage influenza virus, excess visits occurred in all age groups, though the relative increase was greatest and earliest among school-aged children. During periods of documented respiratory syncytial virus (RSV) circulation, increases in fever and respiratory emergency department visits occurred in children under five years of age regardless of influenza circulation. Finally, the researchers found that excess visits to emergency departments for fever and respiratory symptoms preceded deaths from pneumonia or influenza by about two weeks.
What Do These Findings Mean?
These findings indicate that excess emergency department visits for fever and respiratory symptoms can provide a reliable and timely surrogate measure of illness due to influenza. They also provide new insights into how different influenza viruses affect people of different ages and how the timing and progression of each influenza season differs. These results, based on data collected over only five years in one city, might not be generalizable to other settings or years, warn the researchers. However, the present results strongly suggest that the routine monitoring of influenza might be improved by using electronic health-related data, such as emergency department visit data, and by examining it specifically by age group. Furthermore, by showing that school-aged children can be the first people to be affected by seasonal influenza, these results highlight the important role this age group plays in community-wide transmission of influenza, an observation that could influence the implementation of public-health strategies such as vaccination that aim to protect communities during influenza epidemics and pandemics.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040247.
• US Centers for Disease Control and Prevention provides information on influenza for patients and health professionals and on influenza surveillance in the US (in English, Spanish, and several other languages)
• World Health Organization has a fact sheet on influenza and on global surveillance for influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
• The MedlinePlus encyclopedia contains a page on flu (in English and Spanish)
• US National Institute of Allergy and Infectious Diseases has a feature called “focus on flu”
• A detailed report from the US Centers for Disease Control and Prevention titled “Framework for Evaluating Public Health Surveillance Systems for Early Detection of Outbreaks” includes a simple description of syndromic surveillance
• The International Society for Disease Surveillance has a collaborative syndromic surveillance public wiki
• The Anthropology of the Contemporary Research Collaboratory includes working papers and discussions by cultural anthropologists studying modern vital systems security and syndromic surveillance
doi:10.1371/journal.pmed.0040247
PMCID: PMC1939858  PMID: 17683196
22.  Selective Involvement of the Amygdala in Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e499.
Background
Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE.
Methods and Findings
We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 × 10−6 mm2/s; p = 0.006 and 949 × 10−6 mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 × 10−6 mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 × 10−6 mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 × 10−6 mm2/s) and also lower (p = 0.001) than in healthy control participants.
Conclusions
This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.
Patients with SLE who also had antibodies against the NMDA receptor had more severe damage in the amygdala as compared with patients with SLE without these antibodies.
Editors' Summary
Background.
The human body is continually attacked by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of proteins that are unique to the pathogen) but ignore self-antigens. In autoimmune diseases, this ability to discriminate between self and nonself fails for unknown reasons, and the immune system begins to destroy human tissues. In the chronic autoimmune disease systemic lupus erythematosus (SLE or lupus), the immune system attacks the skin, joints, nervous system, and many other organs. Patients with SLE make numerous “autoantibodies” (antibodies are molecules made by the immune system that recognize and attack antigens; autoantibodies attack self-antigens). These autoantibodies start the attack on the body; then other parts of the immune system join in, causing inflammation and forming deposits of immune cells, both of which damage tissues. Common symptoms of SLE include skin rashes and arthritis, but some patients develop NP-SLE, a form of SLE that includes neuropsychiatric symptoms such as amnesia, dementia, mood disorders, strokes, and seizures. There is no cure for SLE, but mild cases are controlled with ibuprofen and other non-steroidal anti-inflammatory drugs; severe cases are kept in check with corticosteroids and other powerful immunosuppressants.
Why Was This Study Done?
In most of the tissues affected by SLE, the damage done by autoantibodies and immune cells can be seen when the tissues are examined with a microscope. But there is little microscopic damage visible in the brains of patients with NP-SLE. More generally, it is unclear how or even whether the immune system affects mental functions and emotion. In this study, researchers used magnetic resonance imaging (MRI) to investigate whether there are any structural changes in the brains of patients with NP-SLE that could explain their neuropsychiatric symptoms. They have also examined whether any changes in the brain can be linked to the presence of autoantibodies that recognize a protein called the NMDA receptor (anti-NMDAR antibodies) that is present on brain cells.
What Did the Researchers Do and Find?
The researchers used an MRI technique called diffusion weighted imaging to examine the brains of several patients with NP-SLE or SLE and the brains of several healthy individuals. Using this technique, it is possible to quantify the amount of structural damage in different regions of the brain. The researchers found no differences in most areas of the brain between the two groups of patients and the healthy controls. However, there were clear signs of damage in the amygdala (the part of the brain that regulates emotions and triggers responses to danger) in the patients with SLE or NP-SLE when compared to the control individuals. The researchers also found that the damage was more severe in the patients who had anti-NMDAR autoantibodies than in those that did not have these autoantibodies.
What Do These Findings Mean?
These findings suggest that autoantibodies produced by patients with SLE specifically damage the amygdala, a discovery that helps to explain some of the neuropsychiatric symptoms of this condition. Previous work has shown that the treatment of mice with anti-NMDAR antibodies and epinephrine, a stress hormone that causes leaks in the blood-brain barrier (antibodies can't usually get into the brain because of this barrier), results in damage to the amygdala and a deficient response to dangerous stimuli. The researchers suggest that a similar series of events might happen in SLE—patients often mention that a period of major stress precedes the development of symptoms. To provide stronger evidence for such a scenario, a detailed study of how stress relates to neuropsychiatric symptoms is needed. The damage to the amygdala (and the lack of damage elsewhere in the brain) and the possible association between brain damage and anti-NMDAR antibodies seen in this small study also need to be confirmed in more patients. Nevertheless, these findings provide an intriguing glimpse into the interplay between the immune system and the brain and into how stress might lead to physical damage in the brain.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030499.
MedlinePlus encyclopedia pages on autoimmunity and on systemic lupus erythematosus
US National Institute of Arthritis and Musculoskeletal and Skin Diseases booklet for patients with SLE
American College of Rheumatology information for patients on SLE
NHS Direct Online Health Encyclopedia pages on SLE
The Lupus Foundation of America information and support for patients with SLE
doi:10.1371/journal.pmed.0030499
PMCID: PMC1702559  PMID: 17177602
23.  Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNFα blockers 
Annals of the Rheumatic Diseases  2005;65(2):191-194.
Objective
To assess the efficacy and safety of vaccination against influenza virus in patients with rheumatoid arthritis, with special emphasis on the effect of disease modifying antirheumatic drugs (DMARDs), including tumour necrosis factor α (TNFα) blockers.
Methods
82 rheumatoid patients and 30 healthy controls were vaccinated with a split‐virion inactivated vaccine containing 15 μg haemagglutinin (HA) per dose of each of B/Hong Kong/330/2001 (HK), A/Panama/2007/99 (PAN), and A/New Caledonian/20/99 (NC). Disease activity was assessed by tender and swollen joint count, morning stiffness, evaluation of pain, Health Assessment Questionnaire, ESR, and C reactive protein on the day of vaccination and six weeks later. Haemagglutination inhibiting (HI) antibodies were tested by a standard WHO procedure. Response was defined as a fourfold or more rise in HI antibodies six weeks after vaccination, or seroconversion in patients with a non‐protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated to assess the immunity of the whole group.
Results
Six weeks after vaccination, a significant increase in GMT for each antigen was observed in both groups, this being higher in the healthy group for HK (p = 0.004). The percentage of responders was lower in rheumatoid patients than healthy controls (significant for HK). The percentage of responders was not affected by prednisone or any DMARD, including methotrexate, infliximab, and etanercept. Indices of disease activity remained unchanged.
Conclusions
Influenza virus vaccine generated a good humoral response in rheumatoid patients, although lower than in healthy controls. The response was not affected by the use of prednisone or DMARDs.
doi:10.1136/ard.2005.036434
PMCID: PMC1798034  PMID: 16014674
rheumatoid arthritis; influenza; anti‐TNFα; vaccination
24.  Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease 
Annals of the Rheumatic Diseases  2005;65(7):913-918.
Objective
to assess the safety and efficacy of influenza vaccination in patients with systemic lupus erythematosus (SLE), and to evaluate the influence of immunosuppressive drugs on the immune response.
Methods
SLE patients (n = 56) and healthy controls (n = 18) were studied. All patients had quiescent disease (SLE disease activity index ⩽5). Four patient groups were defined on the basis of their drug use: (1) no drug treatment; (2) hydroxychloroquine treatment; (3) azathioprine treatment; (4) prednisone treatment. Participants received trivalent influenza subunit vaccine during October/November 2003. Disease activity scores and side effects were recorded. Antibody titres against influenza virus were measured before and 30 days after vaccination using the haemagglutination inhibition assay.
Results
Influenza vaccination did not result in changes in disease activity and was well tolerated. SLE patients had fewer seroconversions or fourfold titre rises for A/H1N1 (p<0.001) and A/H3N2 (p<0.001) than healthy controls, while for B/Hong Kong the difference was of borderline significance (p = 0.051). With regard to immunosuppressive treatment, fewer SLE patients using azathioprine developed fourfold titre rises against A/H3N2 (p = 0.041), and fewer achieved titres of ⩾40 against A/H3N2 (p = 0.030) compared with the other patient groups.
Conclusions
Influenza vaccination in SLE patients with quiescent disease is safe but is less effective than in controls. Use of azathioprine was associated with a trend to decreased vaccination efficacy.
doi:10.1136/ard.2005.043943
PMCID: PMC1798193  PMID: 16322083
SLE; influenza vaccination; safety; efficacy
25.  A Comparative Analysis of Influenza Vaccination Programs 
PLoS Medicine  2006;3(10):e387.
Background
The threat of avian influenza and the 2004–2005 influenza vaccine supply shortage in the United States have sparked a debate about optimal vaccination strategies to reduce the burden of morbidity and mortality caused by the influenza virus.
Methods and Findings
We present a comparative analysis of two classes of suggested vaccination strategies: mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations. Applying the methods of contact network epidemiology to a model of disease transmission in a large urban population, we assume that vaccine supplies are limited and then evaluate the efficacy of these strategies across a wide range of viral transmission rates and for two different age-specific mortality distributions.
We find that the optimal strategy depends critically on the viral transmission level (reproductive rate) of the virus: morbidity-based strategies outperform mortality-based strategies for moderately transmissible strains, while the reverse is true for highly transmissible strains. These results hold for a range of mortality rates reported for prior influenza epidemics and pandemics. Furthermore, we show that vaccination delays and multiple introductions of disease into the community have a more detrimental impact on morbidity-based strategies than mortality-based strategies.
Conclusions
If public health officials have reasonable estimates of the viral transmission rate and the frequency of new introductions into the community prior to an outbreak, then these methods can guide the design of optimal vaccination priorities. When such information is unreliable or not available, as is often the case, this study recommends mortality-based vaccination priorities.
A comparative analysis of two classes of suggested vaccination strategies, mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations.
Editors' Summary
Background.
Influenza—a viral infection of the nose, throat, and airways that is transmitted in airborne droplets released by coughing or sneezing—is a serious public health threat. Most people recover quickly from influenza, but some individuals, especially infants, old people, and individuals with chronic health problems, can develop pneumonia and die. In the US, seasonal outbreaks (epidemics) of flu cause an estimated 36,000 excess deaths annually. And now there are fears that avian influenza might start a human pandemic—a global epidemic that could kill millions. Seasonal outbreaks of influenza occur because flu viruses continually change the viral proteins (antigens) to which the immune system responds. “Antigenic drift”—small changes in these proteins—means that an immune system response that combats flu one year may not provide complete protection the next winter. “Antigenic shift”—large antigen changes—can cause pandemics because communities have no immunity to the changed virus. Annual vaccination with vaccines based on the currently circulating viruses controls seasonal flu epidemics; to control a pandemic, vaccines based on the antigenically altered virus would have to be quickly developed.
Why Was This Study Done?
Most countries target vaccination efforts towards the people most at risk of dying from influenza, and to health-care workers who are likely come into contact with flu patients. But is this the best way to reduce the burden of illness (morbidity) and death (mortality) caused by influenza, particularly at the start of a pandemic, when vaccine would be limited? Old people and infants are much less likely to catch and spread influenza than school children, students, and employed adults, so could vaccination of these sections of the population—instead of those most at risk of death—be the best way to contain influenza outbreaks? In this study, the researchers used an analytical method called “contact network epidemiology” to compare two types of vaccination strategies: the currently favored mortality-based strategy, which targets high-risk individuals, and a morbidity-based strategy, which targets those segments of the community in which most influenza cases occur.
What Did the Researchers Do and Find?
Most models of disease transmission assume that each member of a community is equally likely to infect every other member. But a baby is unlikely to transmit flu to, for example, an unrelated, housebound elderly person. Contact network epidemiology takes the likely relationships between people into account when modeling disease transmission. Using information from Vancouver, British Columbia, Canada, on household size, age distribution, and occupations, and other factors such as school sizes, the researchers built a model population of a quarter of a million interconnected people. They then investigated how different vaccination strategies controlled the spread of influenza in this population. The optimal strategy depended on the level of viral transmissibility—the likelihood that an infectious person transmits influenza to a susceptible individual with whom he or she has contact. For moderately transmissible flu viruses, a morbidity-based vaccination strategy, in which the people most likely to catch the flu are vaccinated, was more effective at containing seasonal and pandemic outbreaks than a mortality-based strategy, in which the people most likely to die if they caught the flu are vaccinated. For highly transmissible strains, this situation was reversed. The level of transmissibility at which this reversal occurred depended on several factors, including whether vaccination was delayed and how many times influenza was introduced into the community.
What Do These Findings Mean?
The researchers tested their models by checking that they could replicate real influenza epidemics and pandemics, but, as with all mathematical models, they included many assumptions about influenza in their calculations, which may affect their results. Also, because the contact network used data from Vancouver, their results might not be applicable to other cities, or to nonurban areas. Nevertheless, their findings have important public health implications. When there are reasonable estimates of the viral transmission rate, and it is known how often influenza is being introduced into a community, contact network models could help public health officials choose between morbidity- and mortality-based vaccination strategies. When the viral transmission rate is unreliable or unavailable (for example, at the start of a pandemic), the best policy would be the currently preferred strategy of mortality-based vaccination. More generally, the use of contact network models should improve estimates of how infectious diseases spread through populations and indicate the best ways to control human epidemics and pandemics.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030387.
US Centers for Disease Control and Prevention information about influenza for patients and professionals, including key facts on vaccination
US National Institute of Allergy and Infectious Diseases feature on seasonal, avian, and pandemic influenza
World Health Organization fact sheet on influenza, with links to information on vaccination
UK Health Protection Agency information on seasonal, avian, and pandemic influenza
MedlinePlus entry on influenza
doi:10.1371/journal.pmed.0030387
PMCID: PMC1584413  PMID: 17020406

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