Gary T. Brice

Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum

Chronic helminth infections induce T‐cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum‐parasitized RBC in Indonesian schoolchildren. Geohelminth‐infected childrens in vitro T‐cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4+CD25hiFOXP3+ T cells was similar regardless of infection status, the suppressive activity differed between geohelminth‐infected and geohelminth‐uninfected groups: Ag‐specific proliferative responses increased upon CD4+CD25hi T‐cell depletion in geohelminth‐infected subjects only. In addition, IFN‐γ production in response to both BCG and parasitized RBC was increased after removal of CD4+CD25hi T cells. These data demonstrate that geohelminth‐associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth‐induced immune modulation may have important consequences for co‐endemic infections and vaccine trials.

The Effect of Three-Monthly Albendazole Treatment on Malarial Parasitemia and Allergy: A Household-Based Cluster-Randomized, Double-Blind, Placebo-Controlled Trial

Background Helminth infections are proposed to have immunomodulatory activities affecting health outcomes either detrimentally or beneficially. We evaluated the effects of albendazole treatment, every three months for 21 months, on STH, malarial parasitemia and allergy. Methods and Findings A household-based cluster-randomized, double-blind, placebo-controlled trial was conducted in an area in Indonesia endemic for STH. Using computer-aided block randomization, 481 households (2022 subjects) and 473 households (1982 subjects) were assigned to receive placebo and albendazole, respectively, every three months. The treatment code was concealed from trial investigators and participants. Malarial parasitemia and malaria-like symptoms were assessed in participants older than four years of age while skin prick test (SPT) to allergens as well as reported symptoms of allergy in children aged 5–15 years. The general impact of treatment on STH prevalence and body mass index (BMI) was evaluated. Primary outcomes were prevalence of malarial parasitemia and SPT to any allergen. Analysis was by intention to treat. At 9 and 21 months post-treatment 80.8% and 80.1% of the study subjects were retained, respectively. The intensive treatment regiment resulted in a reduction in the prevalence of STH by 48% in albendazole and 9% in placebo group. Albendazole treatment led to a transient increase in malarial parasitemia at 6 months post treatment (OR 4.16(1.35–12.80)) and no statistically significant increase in SPT reactivity (OR 1.18(0.74–1.86) at 9 months or 1.37 (0.93–2.01) 21 months). No effect of anthelminthic treatment was found on BMI, reported malaria-like- and allergy symptoms. No adverse effects were reported. Conclusions The study indicates that intensive community treatment of 3 monthly albendazole administration for 21 months over two years leads to a reduction in STH. This degree of reduction appears safe without any increased risk of malaria or allergies. Trial Registration Controlled-Trials.com ISRCTN83830814

Epidemiology of Pathogen-Specific Respiratory Infections among Three US Populations

Background Diagnostic tests for respiratory infections can be costly and time-consuming. Improved characterization of specific respiratory pathogens by identifying frequent signs, symptoms and demographic characteristics, along with improving our understanding of coinfection rates and seasonality, may improve treatment and prevention measures. Methods Febrile respiratory illness (FRI) and severe acute respiratory infection (SARI) surveillance was conducted from October 2011 through March 2013 among three US populations: civilians near the US–Mexico border, Department of Defense (DoD) beneficiaries, and military recruits. Clinical and demographic questionnaire data and respiratory swabs were collected from participants, tested by PCR for nine different respiratory pathogens and summarized. Age stratified characteristics of civilians positive for influenza and recruits positive for rhinovirus were compared to other and no/unknown pathogen. Seasonality and coinfection rates were also described. Results A total of 1444 patients met the FRI or SARI case definition and were enrolled in this study. Influenza signs and symptoms varied across age groups of civilians. Recruits with rhinovirus had higher percentages of pneumonia, cough, shortness of breath, congestion, cough, less fever and longer time to seeking care and were more likely to be male compared to those in the no/unknown pathogen group. Coinfections were found in 6% of all FRI/SARI cases tested and were most frequently seen among children and with rhinovirus infections. Clear seasonal trends were identified for influenza, rhinovirus, and respiratory syncytial virus. Conclusions The age-stratified clinical characteristics associated with influenza suggest that age-specific case definitions may improve influenza surveillance and identification. Improving identification of rhinoviruses, the most frequent respiratory infection among recruits, may be useful for separating out contagious individuals, especially when larger outbreaks occur. Overall, describing the epidemiology of pathogen specific respiratory diseases can help improve clinical diagnoses, establish baselines of infection, identify outbreaks, and help prioritize the development of new vaccines and treatments.

Influenza vaccine effectiveness: Maintained protection throughout the duration of influenza seasons 2010–2011 through 2013–2014

BACKGROUND Factors, such as age, comorbidities, vaccine type, herd immunity, previous influenza exposure, and antigenic shift may impact the immune response to the influenza vaccine, protection against circulating strains, and antibody waning. Evaluating vaccine effectiveness (VE) is important for informing timing of vaccine administration and evaluating overall vaccine benefit. METHODS VE was assessed using febrile respiratory illness surveillance among Department of Defense non-active duty beneficiaries from influenza seasons 2010-2011 through 2013-2014. Respiratory specimens were taken from participants meeting the case definition and tested by polymerase chain reaction for influenza. VE was calculated using logistic regression and by taking 1 minus the odds ratio of being vaccinated in the laboratory confirmed positive influenza cases versus laboratory confirmed negative controls. RESULTS This study included 1486 participants. We found an overall adjusted VE that provided significant and fairly consistent protection ranging from 54% to 67% during 0-180days postvaccination. This VE dropped to -11% (95% confidence interval: -102% to 39%) during 181-365days. CONCLUSIONS Our study found moderate VE up to 6months postvaccination. Since the influenza season starts at different times each year, optimal timing is difficult to predict. Consequently, early influenza vaccination may still offer the best overall protection.

Frequency of influenza H3N2 intra-subtype reassortment: attributes and implications of reassortant spread

BackgroundIncreasing evidence suggests that influenza reassortment not only contributes to the emergence of new human pandemics but also plays an important role in seasonal influenza epidemics, disease severity, evolution, and vaccine efficacy. We studied this process within 2091 H3N2 full genomes utilizing a combination of the latest reassortment detection tools and more conventional phylogenetic analyses.ResultsWe found that the amount of H3N2 intra-subtype reassortment depended on the number of sampled genomes, occurred with a steady frequency of 3.35%, and was not affected by the geographical origins, evolutionary patterns, or previous reassortment history of the virus. We identified both single reassortant genomes and reassortant clades, each clade representing one reassortment event followed by successful spread of the reassorted variant in the human population. It was this spread that was mainly responsible for the observed high presence of H3N2 intra-subtype reassortant genomes. The successfully spread variants were generally sampled within one year of their formation, highlighting the risk of their rapid spread but also presenting an opportunity for their rapid detection. Simultaneous spread of several different reassortant lineages was observed, and despite their limited average lifetime, second and third generation reassortment was detected, as well as reassortment between viruses belonging to different vaccine-associated clades, likely displaying differing antigenic properties. Some of the spreading reassortants remained confined to certain geographical regions, while others, sharing common properties in amino acid positions of the HA, NA, and PB2 segments, were found throughout the world.ConclusionsDetailed surveillance of seasonal influenza reassortment patterns and variant properties may provide unique information needed for prediction of spread and construction of future influenza vaccines.

Performance of the Quidel Sofia rapid influenza diagnostic test during the 2012–2013 and 2013–2014 influenza seasons

The Quidel Sofia Influenza A+B Fluorescent Immunoassay was used to test nasal swab specimens from patients with influenza‐like illness at US–Mexico border‐area clinics in the 2012–2013 and 2013–2014 influenza seasons. Compared with real‐time reverse transcription polymerase chain reaction, the overall sensitivities and specificities were 83% and 81%, and 62% and 93%, respectively.

Seroprotective Antibodies to 2011 Variant Influenza A(H3N2v) and Seasonal Influenza A(H3N2) among Three Age Groups of US Department of Defense Service Members

Background In 2011, a new variant of influenza A(H3N2) emerged that contained a recombination of genes from swine H3N2 viruses and the matrix (M) gene of influenza A(H1N1)pdm09 virus. New combinations and variants of pre-existing influenza viruses are worrisome if there is low or nonexistent immunity in a population, which increases chances for an outbreak or pandemic. Methods Sera collected in 2011 were obtained from US Department of Defense service members in three age groups: 19–21 years, 32–33 years, and 47–48 years. Pre- and post-vaccination samples were available for the youngest age group, and postvaccination samples for the two older groups. Specimens were tested using microneutralization assays for antibody titers against H3N2v (A/Indiana/10/2011) and seasonal H3N2 virus (A/Perth/16/2009). Results The youngest age group had significantly (p<0.05) higher geometric mean titers for H3N2v with 165 (95% confidence interval [CI]: 105–225) compared with the two older groups, aged 32–33 and 47–48 years, who had geometric mean titers of 68 (95% CI: 55–82) and 46 (95% CI: 24–65), respectively. Similarly, the youngest age group also had the highest geometric mean titers for seasonal H3N2. In the youngest age group, the proportion of patients who seroconverted after vaccination was 12% for H3N2v and 27% for seasonal H3N2. Discussion Our results were similar to previous studies that found highest seroprotection among young adults and decreasing titers among older adults. The proportion of 19- to 21-year-olds who seroconverted after seasonal vaccination was low and similar to previous findings. Improving our understanding of H3N2v immunity among different age groups in the United States can help inform vaccination plans if H3N2v becomes more transmissible in the future.

Live adenovirus types 4 and 7 not detected in the blood of vaccine recipients

Military recruits are highly susceptible to adenovirus-related espiratory infections, likely due to the unique operating environents and training-related stress and fatigue [1]. The associated orbidity results in lost training days and although rare, even death 2]. Adenovirus infections decreased dramatically at recruit trainng centers between 1971 and 1996 following immunization with nteric vaccines against adenovirus types 4 and 7 [3]. However, he disease re-emerged when production ceased and vaccination as discontinued. In 2004, a clinical trial was initiated to test live, ral adenovirus types 4 and 7 vaccines in military recruits, followed y a phase III trial that resulted in Food and Drug Administration pproval of the vaccines in 2011 [4]. Vaccination was reinstated at ecruit training centers beginning around October 2011. Military recruits are an important source of blood donations or military treatment facilities for use in retired military and ependent populations, many of whom are immunocompromised. denovirus has been identified as an emerging pathogen in mmunocompromised patients [5], however there are no published ata regarding adenovirus vaccine-generated viremia. Currently, here is no published data regarding adenovirus vaccine-generated iremia, although, there have been a few studies looking at viremia ollowing administration of other live-virus vaccines. Wilkins et al. solated rubella virus 10 days post-vaccination, and posit that iremia occurs in almost every susceptible recipient but is low rade, transient, or both [6]. Another study of a live recombinant accine against West Nile Virus found that vaccine was cleared rom the blood by day 10, with the mean number of viremic days etween 3.7 and 5.1 [7]. Finally, a 1966 study elucidated free virus n the blood as early as the third day following vaccination with ype 2 oral poliovirus vaccine. Fifty-five percent of subjects receivng this vaccine were shown to be viremic, although this often was nterspersed with intervening viremia-free periods [8]. Currently, the de facto time to blood donation after live oral adeovirus vaccination is 30 days, which is a relatively arbitrary time rame that hinders blood donation activities at many recruit trainng centers. We conducted a study at Marine Corps Recruit Depot an Diego to determine the incidence and duration of vaccinenduced viremia, as well as identify any circulating strains of denovirus. Two hundred and forty-nine male recruits were enrolled at he male-only training facility. Prevaccination blood samples were btained upon arrival. Available data indicate that viremia is typcally detected 3–10 days postvaccination; hence, blood samples ere collected on postvaccination days 3 and 8 [6–8]. Additionally, lood samples were collected on postvaccination days 30 and 61 or surveillance purposes. [

ILI and SARI Surveillance along the California & Arizona Borders with Mexico, 2011-12

Objective To identify the pathogens responsible for influenza-like illness (ILI) and severe acute respiratory illness (SARI) along the U.S.-Mexico border region in San Diego and Imperial Counties, CA and Pima County, AZ. Introduction National borders do not prevent the transmission of pathogens and associated vectors among border populations. The Naval Health Research Center (NHRC) has collaborated with the Mexican Secretariat of Health, the U. S. Department of State’s Biosecurity Engagement Program (BEP) and the U. S. Centers for Disease Control and Prevention (CDC) in concert with local health officials to conduct ILI surveillance (since 2004) and SARI surveillance (since 2009) in the border region. Methods Respiratory swabs were collected from patients with ILI (fever ≥ 100F, and sore throat or cough) or SARI (≥ 5 y.o.: ILI with hospital admission; < 5 y.o.: clinical suspicion of pneumonia with hospital admission) and stored at −70C. Specimens were tested with molecular techniques, viral and bacterial culture. Results NHRC received and tested 295 ILI specimens collected from four surveillance sites in 2011–12. Demographics: 53% female, 47% male; 36% 0–4 yrs old, 50% 5–24 yrs old, 8% 25–49 yrs old, 4% 50–64 yrs old, 2% >64 yrs old. Pathogens identified included influenza A (15%); rhinovirus (8%); respiratory syncytial virus (RSV) (7%); adenovirus (6%); influenza B (4%) and parainfluenza virus (PIV) 1; (4%). 335 SARI specimens were collected from 6 sites. Demographics: 52% female, 48% male; 41% 0–4 yrs old; 9% 5–24 yrs old, 12% 25–49 yrs old, 11% 50–64 yrs old, 28% >64 yrs old. Pathogens identified included RSV (17%); rhinovirus (10%); influenza A (9%); adenovirus (6%); influenza B (2%) and PIV 1 (1%). Conclusions In 2011–12, our surveillance identified a difference in the proportion of respiratory pathogens affecting outpatients and inpatients. Influenza A was isolated more frequently in outpatients, whereas RSV was more frequent in hospitalized patients. We also noted an increased proportion of specimens from the 50–64 yr old and the >64 yr old age groups in the SARI surveillance, whereas 86% of the ILI specimens are from patients 24 yrs old or less. Additional benefits of this collaborative surveillance have been the cooperation, joint training and communication between the participating entities. These pre-established lines of communication are invaluable during a public health emergency, which was demonstrated during the recent influenza pandemic.

Effectiveness of the 2011-12 Influenza Vaccine: Data from US Military Dependents and US-Mexico Border Civilians.

Objective To assess effectiveness of the influenza vaccine among US military dependents and US-Mexico Border populations during the 2011–12 influenza season. Introduction As a result of antigenic drift of the influenza viruses, the composition of the influenza vaccine is updated yearly to match circulating strains. Consequently, there is need to assess the effectiveness of the influenza vaccine (VE) on a yearly basis. Ongoing febrile respiratory illness (FRI) surveillance captures data and specimens that are leveraged to estimate influenza VE on an annual basis. Methods Data from ongoing FRI surveillance at US Military and US-Mexico border clinics were used to estimate VE. We conducted a case–control study between weeks 3 and 17 of the 2011–12 influenza season. Specimens were collected from individuals meeting FRI case definition (fever ≥ 100.0 F with either cough or sore throat). Cases were laboratory confirmed influenza infection and controls were negative for influenza. Interviewer-administered questionnaires collected information on patient demographics and clinical factors and vaccination status. Logistic regression was used to calculate the crude and adjusted odds ratios (OR) and VE was computed as (1-OR) × 100%. Vaccine protection was assumed to begin 14 days post-vaccination. Results A total of 155 influenza positive cases and 429 influenza negative controls were included in the analysis - 72 cases were influenza A(H3N2), 38 cases were influenza A(H1N1), and 45 cases were influenza B. Overall adjusted VE against laboratory-confirmed influenza was 46% (95% CI, 19–64%); unadjusted was 39% (95% CI, 11–58%). Influenza subtype analyses revealed moderate protection against A/H3 and A/H1 and lower protection against B. Lowest estimated VE was seen in older individuals, age 65 and older. Conclusions Influenza vaccination was moderately protective against laboratory confirmed influenza in this population. Continued surveillance is important in monitoring the effectiveness of the influenza vaccine.