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The spread of white-nose syndrome into western North America has caused concerns that bat species inhabiting the region will soon experience population declines like those seen to the east. However, much of the region lacks baseline estimates of abundance for bats believed to be susceptible to WNS due to a scarcity of known hibernacula, where populations are traditionally monitored. The goal of this study was to determine the abundance, roost fidelity, and activity patterns of summer colonies of female little brown myotis (Myotis lucifugus) in an area with no known hibernacula. To accomplish this, we subcutaneously implanted passive integrated transponder (PIT) tags into 297 female little brown myotis from 2015 to 2018 and installed radio-frequency identification (RFID) readers and antennas inside three maternity roosts in Yellowstone National Park. Bats occupied RFID-monitored roosts on 32% of days and were never detected at maternity roosts located > 16 km from where they were tagged. Roost fidelity varied throughout summer and was greatest during late gestation and early lactation. This allowed us to combine nightly scans of RFID-tagged bats with visual emergence counts to estimate the population of bats using two roosts located >16 km apart during 2017–2018. Population estimates of both colonies were markedly higher (N* = 208 ± 6 bats and N* = 836 ± 67 bats during 2018) than the number of bats seen during evening emergence (high counts of 127 and 222, respectively). Nocturnal visits of tagged bats to these roosts increased around the time of parturition, indicative of bats returning to nurse young. These data show that emergence count and PIT tag data can be combined to monitor bat population abundance and activity patterns in areas where hibernacula are absent or where their locations are unknown. [ABSTRACT FROM AUTHOR]

The spread of white-nose syndrome into western North America has caused concerns that bat species inhabiting the region will soon experience population declines like those seen to the east. However, much of the region lacks baseline estimates of abundance for bats believed to be susceptible to WNS due to a scarcity of known hibernacula, where populations are traditionally monitored. The goal of this study was to determine the abundance, roost fidelity, and activity patterns of summer colonies of female little brown myotis (Myotis lucifugus) in an area with no known hibernacula. To accomplish this, we subcutaneously implanted passive integrated transponder (PIT) tags into 297 female little brown myotis from 2015 to 2018 and installed radio-frequency identification (RFID) readers and antennas inside three maternity roosts in Yellowstone National Park. Bats occupied RFID-monitored roosts on 32% of days and were never detected at maternity roosts located > 16 km from where they were tagged. Roost fidelity varied throughout summer and was greatest during late gestation and early lactation. This allowed us to combine nightly scans of RFID-tagged bats with visual emergence counts to estimate the population of bats using two roosts located >16 km apart during 2017–2018. Population estimates of both colonies were markedly higher (N* = 208 ± 6 bats and N* = 836 ± 67 bats during 2018) than the number of bats seen during evening emergence (high counts of 127 and 222, respectively). Nocturnal visits of tagged bats to these roosts increased around the time of parturition, indicative of bats returning to nurse young. These data show that emergence count and PIT tag data can be combined to monitor bat population abundance and activity patterns in areas where hibernacula are absent or where their locations are unknown. [ABSTRACT FROM AUTHOR]

Bats are a group of mammals well known for forming dynamic social groups. Studies of bat social structures are often based upon the frequency at which bats occupy the same roosts because observing bats directly is not always possible. However, it is not always clear how closely bats occupying the same roost associate with each other, obscuring whether associations result from social relationships or factors such as shared preferences for roosts. Our goal was to determine if bats cohabitating buildings were also found together inside roosts by using anti‐collision technology for PIT tags, which enables simultaneous detection of multiple tags. We PIT‐tagged 293 female little brown myotis (Myotis lucifugus) and installed antennas within two buildings used as maternity roosts in Yellowstone National Park. Antennas were positioned at roost entryways to generate cohabitation networks and along regions of attic ceilings in each building to generate intraroost networks based on proximity of bats to each other. We found that intraroost and cohabitation networks of buildings were significantly correlated, with the same bats tending to be linked in both networks, but that bats cohabitating the same building often roosted apart, leading to differing assessments of social structure. Cohabitation rates implied that bats associate with a greater number of their roost‐mates than was supported by observations within the roost. This caused social networks built upon roost cohabitation rates to be denser, smaller in diameter, and contain nodes with higher average degree centrality. These results show that roost cohabitation does not reflect preference for roost‐mates in little brown myotis, as is often inferred from similar studies, and that social network analyses based on cohabitation may provide misleading results. [ABSTRACT FROM AUTHOR]

There is limited information on the antigen specificity and functional potential of the influenza virus-specific CD4+ T-cell repertoire in humans. Here, enzyme-linked immunospot assays were used to examine circulating CD4+ T-cell specificities for influenza virus directly ex vivo in healthy adults. Our studies revealed CD4+ T-cell reactivity to multiple influenza virus proteins, including hemagglutinins, neuraminidases, M1 proteins, and nucleoproteins. Unexpectedly, the immunodominance hierarchies and functional potential of cells reactive toward influenza A virus were distinct from those toward influenza B virus. We also identified influenza virus-specific cells producing granzyme B. Our findings revealed individual and virus-specific patterns that may differentially poise humans to respond to infection or vaccination. [ABSTRACT FROM AUTHOR]

Background Influenza A viruses of the H5 subtype have been identified as important targets for development of vaccines. Achievement of potentially protective antibody responses against pandemic strains has usually required the use of adjuvants. Objectives We evaluated a candidate A/Indonesia/05/2005 (H5) vaccine generated by baculovirus expression of recombinant hemagglutinin (HA) protein with or without stable emulsion (SE) as an adjuvant. Methods Healthy subjects 18–49 years old were randomized (1:1:1:1) to receive two doses of rHA at 7.5 ug per dose (no adjuvant), or 3.8 ug, 7.5 ug, or 15 ug per dose formulated with 2% SE separated by 21 days, and serum from day 0, 21, 42, and 201 assessed by hemagglutination-inhibition. Results 341 subjects were enrolled in the study and 321 received two doses of vaccine. Vaccination was well tolerated in all groups. After two doses, seroconversion was noted in only 9% (95% confidence interval 4%, 17%) of recipients of unadjuvanted vaccine at 7.5 ug, but in 70% (59%, 80%), 76% (65%, 85%), and 83% (73%, 91%) of those receiving adjuvanted vaccine at 3.8 ug, 7.5 ug, or 15 ug respectively. Conclusions Stable emulsion alone is an effective adjuvant for rH5 vaccine in healthy adults. All three adjuvanted dose groups met the current criterion for seroconversion rate for pandemic vaccines. This dose-ranging study also identified a group (15 ug per dose formulated with 2% SE) that met the criteria for both seroconversion and percentage of subjects achieving an HI antibody titer ⩾ 40. These Phase 2 data support the further clinical development of SE adjuvanted Panblok H5. Clinical trial registration: NCT01612000 . The protocol was approved by the relevant Institutional Review Board for each study site, and the study was conducted in accordance with the Declaration of Helsinki, International Conference of Harmonisation – Good Clinical Practice, and all applicable laws and regulations. All participants provided written informed consent before study procedures. [ABSTRACT FROM AUTHOR]

A substantial body of work exists describing timing of migration and hibernation among bats in eastern North America, but less is known about these events among bats inhabiting the Rocky Mountain region. Yellowstone National Park is a geothermally influenced landscape comprised of diverse habitats, creating the opportunity for unique behaviors to develop among local bat populations. We identified the timing of migration for the local bat community and determined if bats overwinter in Yellowstone. To accomplish this, we radiotracked 7 little brown myotis (Myotis lucifugus), 5 western long-eared myotis (M. evotis), 4 big brown bats (Eptesicus fuscus), 4 silver-haired bats (Lasionycteris noctivagans), and 1 western small-footed myotis (M. ciliolabrum) from August to September 2010 and September to October 2011. We also used acoustic detectors to record bat activity from November through April 2011-2014 and sampled abundance of nocturnal insects using black-light traps from 2011 to 2012. Although availability of insects declined rapidly during August and afterward, several bat species remained active throughout autumn and winter. Bat activity was recorded during all months, even during periods of extreme cold. Radiotagged big brown bats, little brown myotis, and western small-footed myotis remained active in the study area throughout October, after the 1st snowfall of the season. While data for activity patterns in late autumn and winter prevented an estimation of the onset of hibernation, spring emergence occurred in April despite persistence of winter conditions. These data provide insights into the migration and hibernation strategies of bat populations in the Rocky Mountains and highlight gaps in our understanding of seasonal changes in these species. [ABSTRACT FROM AUTHOR]

The article focuses on development of vaccination for Influenza disease. Topics discussed include observation of influenza pandemics with occurrence of neuraminidase, avoidance of recommendation for vaccines usage by the U.S. Advisory Committee on Immunization Practices (ACIP), involvement of cellular immunity in production of vaccines, illustration of several licensed influenza vaccines in the U.S. such as Fluarix and description of vaccine effectiveness with reduction in cardiovascular issues.

The seasonal availability of food resources is an important factor shaping the life-history strategies of organisms. During times of nutritional restriction, physiological trade-offs can induce periods of immune suppression, thereby increasing susceptibility to infectious disease. Our goal was to provide a conceptual framework describing how the endemic level bovine brucellosis ( Brucella abortus) may be maintained in Yellowstone bison based on the seasonality of food resources and the life-history strategies of the host and pathogen. Our analysis was based on active B. abortus infection (measured via bacterial culture), nutritional indicators (measured as metabolites and hormones in plasma), and carcass measurements of 402 slaughtered bison. Data from Yellowstone bison were used to investigate (1) whether seasonal changes in diet quality affect nutritional condition and coincide with the reproductive needs of female bison; (2) whether active B. abortus infection and infection intensities vary with host nutrition and nutritional condition; and (3) the evidence for seasonal changes in immune responses, which may offer protection against B. abortus, in relation to nutritional condition. Female bison experienced a decline in nutritional condition during winter as reproductive demands of late gestation increased while forage quality and availability declined. Active B. abortus infection was negatively associated with bison age and nutritional condition, with the intensity of infection negatively associated with indicators of nutrition (e.g., dietary protein and energy) and body weight. Data suggest that protective cell-mediated immune responses may be reduced during the B. abortus transmission period, which coincides with nutritional insufficiencies and elevated reproductive demands during spring. Our results illustrate how seasonal food restriction can drive physiological trade-offs that suppress immune function and create infection and transmission opportunities for pathogens. [ABSTRACT FROM AUTHOR]

Background: Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine.Methods: Forty-eight adults aged 18-49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18-49 (n=16), 50-64 (n=19), and 65-85 (n=19) years, received 2 doses of vaccine containing 50 µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose.Results: Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18-49, 50-64, and 65-83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of ≥200.Conclusions: The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks. Clinical Trials Registration. NCT01168401. [ABSTRACT FROM AUTHOR]

Background. Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine.Methods. Forty-eight adults aged 18–49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18–49 (n = 16), 50–64 (n = 19), and 65–85 (n = 19) years, received 2 doses of vaccine containing 50 µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose.Results. Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18–49, 50–64, and 65–83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of ≥200.Conclusions. The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks.Clinical Trials Registration. NCT01168401. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are critical inducers of the adaptive immune response. Extensive characterization of tissue-resident and monocyte-derived DC has revealed diverse stimulatory and regulatory actions, although the role of peripheral blood dendritic cells (PBDC) in maintaining homeostasis remains unclear. Examination of various myeloid (CD11c+CD303-) and plasmacytoid (CD11c-CD303+) DC populations in the peripheral blood of seasonal trivalent inactivated influenza vaccine recipients revealed a transient decrease in the frequency of CD11c+CD1c- myeloid DC subsets 5-10 days following vaccination, including both CD141+ and CD141- myeloid DC subsets of this population. These populations rebounded by 1 month, while plasmacytoid DC remained stable. The magnitude of the decrease in the CD141+ myeloid DC subset at d5-7 significantly correlated with the induction of influenza specific serum antibodies measured at 1 month following vaccination. These results demonstrate a mobilization of peripheral blood myeloid DC following vaccination and indicate these cells are potential biomarkers of immune response. [ABSTRACT FROM AUTHOR]

Highlights: [•] We evaluated baculovirus-expressed recombinant H5 hemagglutinin vaccine with the adjuvant GLE/SE. [•] Adjuvanted vaccine was substantially more immunogenic at all dose levels than the unadjuvanted vaccine. [•] Even at the lowest dose of vaccine administered, serum HAI antibody responses of ≥1:40 were seen in 72% of subjects. [•] GLA/SE is an effective adjuvant for recombinant H5 HA. [•] Baculovirus-expressed HA vaccine has promise for pandemic preparedness as well. [ABSTRACT FROM AUTHOR]

In a case-control study at 4 US centers, the effectiveness of influenza vaccine against medically attended polymerase chain reaction–confirmed influenza was 60% (95% confidence interval, 53%–66%). Significant effectiveness was demonstrated in young children, adolescents, and adults, with a lower estimate for those aged ≥65.Background. Influenza vaccines may be reformulated annually because of antigenic drift in influenza viruses. However, the relationship between antigenic characteristics of circulating viruses and vaccine effectiveness (VE) is not well understood. We conducted an assessment of the effectiveness of US influenza vaccines during the 2010–2011 season.Methods. We performed a case–control study comparing vaccination histories between subjects with acute respiratory illness with positive real-time reverse transcription polymerase chain reaction for influenza and influenza test-negative controls. Subjects with acute respiratory illness of ≤7 days duration were enrolled in hospitals, emergency departments, or outpatient clinics in communities in 4 states. History of immunization with the 2010–2011 vaccine was ascertained from vaccine registries or medical records. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, age, race, insurance status, enrollment site, and presence of a high-risk medical condition.Results. A total of 1040 influenza-positive cases and 3717 influenza-negative controls were included from the influenza season, including 373 cases of influenza A(H1N1), 334 cases of influenza A(H3N2), and 333 cases of influenza B. Overall adjusted VE was 60% (95% confidence interval [CI], 53%–66%). Age-specific VE estimates ranged from 69% (95% CI, 56%–77%) in children aged 6 months–8 years to 38% (95% CI, −16% to 67%) in adults aged ≥65 years.Conclusions. The US 2010–2011 influenza vaccines were moderately effective in preventing medically attended influenza during a season when all 3 vaccine strains were antigenically similar to circulating viruses. Continued monitoring of influenza vaccines in all age groups is important, particularly as new vaccines are introduced. [ABSTRACT FROM PUBLISHER]

Abstract: Background: We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C. Methods: In a dose escalation trial, 112 healthy subjects 18–49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20μg. VAX128C was selected for second study performed in 100 subjects 18–64 years old comparing 1.25 and 2.5μg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured. Conclusions: In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5μg in adults 18–49. In adults ≥65 years, the vaccines doses of ≥4μg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8μg, VAX128B to 16μg and VAX128C to 20μg. Dose escalation for VAX128A was stopped at 8μg because one subject had temperature 101.6°F associated with a high CRP response, VAX128B was stopped at 16μg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20μg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5μg. The peak GMT was 385 (95%CI 272–546), 79% (71–87%) seroconversion and 92% (84–96%) seroprotection. Discussion: Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology. [Copyright &y& Elsevier]

Summary 1. Disease management along the boundaries of wildlife reserves is a growing conservation problem worldwide, as infected wildlife can migrate outside protected areas and pose a threat to livestock and human health. The bison Bison bison population in Yellowstone National Park has long been infected with Brucella abortus, but culling of Yellowstone bison to prevent transmission to cattle has been ineffective at reducing brucellosis infection. This management strategy is negatively affecting long-term bison conservation because of difficulties in diagnosing actively infected animals. 2. We integrated age-specific serology and B. abortus culture results from slaughtered Yellowstone bison to estimate probabilities of active brucellosis infection using a Bayesian framework. Infection probabilities were associated with age in young bison (0-5 years old) and with elevated antibody levels in older bison (>5 years old). Our results indicate that Yellowstone bison acquire B. abortus infection early in life but typically recover as they grow older. 3. A tool was developed to allow bison management to better reflect the probability that particular animals are infective, with the aim of conserving Yellowstone bison while reducing the risk of brucellosis transmission to cattle. Combining selective removal of infectious bison with additional management practices, such as vaccination, has the potential to advance an effective brucellosis reduction programme. 4. Synthesis and applications. We conclude that active B. abortus infection in Yellowstone bison is age dependent, which allows true infection probabilities to be estimated based on age and quantitative diagnostic tests. These findings have important application to disease management worldwide where accurate diagnostic tests for wildlife are unavailable. Estimation of true infection probabilities can replace culling practices that conflict with wildlife conservation. The ability to identify infective individuals can improve management practices that support conservation, particularly when human health is at risk or endangered wildlife species are involved. [ABSTRACT FROM AUTHOR]

Abstract: Background: Development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production is a high priority. We conducted this study to determine the protective efficacy a recombinant, baculovirus-expressed seasonal trivalent influenza virus hemagglutinin (rHA0) vaccine (FluBlok®). Methods: Healthy adult subjects at 24 centers across the US were randomly assigned to receive a single injection of saline placebo (2304 subjects), or trivalent FluBlok containing 45 mcg of each rHA0 component (2344 subjects). Serum samples for assessment of immune responses by hemagglutination-inhibition (HAI) were taken from a subset of subjects before and 28 days after immunization. Subjects were followed during the 2007–2008 influenza season and combined nasal and throat swabs for virus isolation were obtained from subjects reporting influenza-like illness. Results: Rates of local and systemic side effects were low, and the rates of systemic side effects were similar in the vaccine and placebo groups. HAI antibody responses were seen in 78%, 81%, and 52% of FluBlok recipients to the H1, H3, and B components, respectively. FluBlok was 44.6% (95% CI, 18.8%, 62.6%) effective in preventing culture-confirmed influenza meeting the CDC influenza-like illness case definition despite significant antigenic mismatch between the vaccine antigens and circulating viruses. Conclusions: Trivalent rHA0 vaccine was safe, immunogenic and effective in the prevention of culture confirmed influenza illness, including protection against drift variants. [Copyright &y& Elsevier]

Abstract: Background: Influenza vaccines perform poorly in the elderly with reduced serological response and vaccine efficacy. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in Escherichia coli. Methods: 120 subjects ≥65 years old were enrolled at three clinical centers. VAX125 vaccine was administered at doses of 0.5, 1, 2, 3, 5 or 8μg delivered i.m. as a single dose vaccination on Day 0 using a dose-escalation with 20 subjects in each dose level. Subjects were followed for adverse events and sera were tested by hemagglutination-inhibition (HAI) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP) and anti-flagellin antibody were also assessed. Results: The mean age was 71 years. The vaccine was well tolerated at all dose levels, with no more than mild to moderate local or systemic symptoms. The geometric mean titers (GMT) increased in all dose groups. In the 5μg group the day 14 post-vaccination HAI titer was 1:226 showing a 12-fold increase over baseline. The 8μg group showed a similar post-vaccination GMT increase (∼8-fold). In the combined 5 and 8μg groups, the seroconversion rate was 75% and the seroprotection rate was 98%. Conclusions: A 5μg dose of VAX125 was safe and able to induce a greater than 10-fold increase HAI antibody levels and nearly complete seroprotection in subjects over 65 years old. The use of flagellin to adjuvant influenza vaccines via the TLR5 innate immune pathway appears to be a useful approach to overcome poor immune responses in the elderly. VAX125 is a promising new candidate for prevention of influenza A disease in both young adults and the elderly. [Copyright &y& Elsevier]

Abstract: Background: The need for worldwide seasonal and pandemic vaccine production has increased interest in the development of innovative technologies for influenza vaccine production. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in E. coli. Methods: 128 healthy adult subjects 18–49 years old were enrolled in a clinical trial conducted in three stages at a single center. Stage 1 was an open-label, dose escalation study in which the VAX125 vaccine was administered intramuscularly (im) at doses of 0.1μg, 0.3μg, 1μg, 2μg, 3μg, 5μg and 8μg to groups of 8 subjects each. Stage 2 was a double-blind, placebo-controlled study in which subjects were randomized to receive 1.0μg and 2.0μg VAX125 vaccine doses or placebo, with 16 subjects per group. Finally, an additional 24 subjects received a 0.5μg dose of VAX125 in stage 3, which was a non-randomized, open label study. In all parts subjects were followed for adverse events and sera was tested by hemagglutination-inhibition (HAI) and microneutralization (MN) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP), cytokine levels, and anti-flagellin antibody were also assessed. Results: Vaccine was generally well tolerated and there were no serious adverse events. Pain at the injection site was the most common local adverse event, and was mild or moderate in intensity. Systemic symptoms after vaccination include fatigue and headache, and two subjects, who received either 3 or 8μg, had moderately severe systemic symptoms accompanied by substantial increases in serum CRP. Serum antibody responses against SI were seen by HAI and MN in most study subjects, with the geometric mean titer of post vaccination antibody increasing in a dose-dependent fashion. Overall, four-fold or greater serum HAI responses were seen in 61 of 96 (64%) subjects who received doses of 0.5μg or greater, including in 46 of 72 subjects who received doses from 0.5μg to 2μg. Conclusions: The globular head of the influenza HA expressed in a prokaryotic system was able to induce a functional antibody response against native virions. Vigorous responses were seen at relatively low doses of HA antigen suggesting that the addition of flagellin provided a substantial adjuvanting effect. The high levels of immune response at low doses of antigen and the relative ease of production associated with E. coli expression suggests that this approach may represent an effective strategy for enhancing the global influenza vaccine supply. [Copyright &y& Elsevier]

Yellowstone bison Bison bison are chronically infected with brucellosis (caused by the bacterium Brucella abortus), which raises concerns about possible transmission to cattle when they migrate to winter ranges outside the Yellowstone National Park. We monitored bison from April to mid-June during 2004-2007 to estimate the timing and location of parturition events that may shed tissues infected by B. abortus. Observed abortions (N¼29) occurred from January through 19 May, while peak calving (80% of births) occurred from 25 April to 26 May, and calving was finished by 5 June. Observed parturition events (N¼115) occurred in the Park and on the Horse Butte peninsula in Montana, USA, where cattle were not present at any time of the year. Allowing bison to occupy public lands outside the Park where cattle are never present (e.g. Horse Butte peninsula) until most bison calving is completed (late May or early June) is not expected to significantly increase the risk of brucellosis transmission from bison to cattle because: 1) bison parturition is essentially completed weeks before cattle occupy nearby ranges, 2) female bison meticulously consume birthing tissues, 3) ultraviolet light and heat degrade B. abortus on tissues, vegetation and soil, 4) scavengers remove fetuses and remaining birth tissues and 5) management maintains separation between bison and cattle on nearby ranges. Allowing bison to occupy public lands outside the Park through their calving season will help conserve bison migratory behaviour and reduce stress on pregnant females and their newborn calves, while still minimizing the risk of brucellosis transmission to cattle. [ABSTRACT FROM AUTHOR]

Abstract: A total of 600 healthy adults ≥65 years were randomized to receive 2 vaccinations 1 month apart of a subvirion avian influenza A/H5N1 vaccine containing 3.75, 7.5, 15, or 45μg of hemagglutinin (HA) with or without aluminum hydroxide (AlOH). All formulations were safe. Groups given the vaccine with AlOH had more injection site discomfort. Dose-related increases in antibody responses were noted after the second vaccination. Antibody responses to the vaccine were not enhanced by AlOH at any HA dose level. A microneutralization titer ≥40 was observed in 36% and 40% of subjects who received 45μg of HA with or without AlOH, respectively. [Copyright &y& Elsevier]

Background. Influenza-associated morbidity and mortality has not decreased in the last decade, despite increased receipt of vaccine. To improve the immunogenicity of influenza vaccine, a high-dose (HD) trivalent, inactivated influenza vaccine was developed. Methods. A multicenter, randomized, double-blind controlled study was conducted to compare HD vaccine (which contains 60 mg of hemagglutinin per strain) with the licensed standard-dose (SD) vaccine (which contains 15 mg of hemagglutinin per strain) in adults ⩾65 years of age. Results. HD vaccine was administered to 2575 subjects, and SD vaccine was administered to 1262 subjects. There was a statistically significant increase in the rates of seroconversion and mean hemagglutination inhibition titers at day 28 after vaccination among those who received HD vaccine, compared with those who received SD vaccine. Mean postvaccination titers for individuals who received HD vaccine were 116 for H1N1, 609 for H3N2, and 69 for B strain; for those who received SD vaccine, mean postvaccination titers were as 67 for H1N1, 333 for H3N2, and 52 for B strain. The HD vaccine met superiority criteria for both A strains, and the responses for B strain met noninferiority criteria. Seroprotection rates were also higher for those who received HD vaccine than for those who received SD vaccine vaccine, for all strains. Local reactions were more frequent in individuals who received HD vaccine, but the reactions were mild to moderate. Conclusions. There was a statistically significant increase in the level of antibody response induced by HD influenza vaccine, compared with that induced by SD vaccine, without an attendant increase in the rate or severity of clinically relevant adverse reactions. These results suggest that the high-dose vaccine may provide improved protective benefits for older adults. [ABSTRACT FROM AUTHOR]

The article describes the discovery of the Plains Spadefoot (Spea bombifrons) in Yellowstone National Park (YNP) in the U.S. Topics covered include natural occurrence of S. bombifrons and S. intermontana in Wyoming, Montana and Idaho, observation of a metamorphosed spadefoot in Fairy Creek in summer of 2013, collection of samples in May 2014, and identification of the species using genetic analysis. It also mentions the observed breeding activity and the breeding site's characteristics.

Previously, we evaluated 2 doses of H5N1 influenza vaccine in persons 18-64 years of age (placebo and 7.5-, 15-, 45-, or 90-µg doses), separated by 28 days. In this study, 337 participants received a third dose, 6 months thereafter. Microneutralization (MN) and hemagglutination-inhibition geometric mean titers (GMTs) of antibody declined before the third dose. Twenty-eight days after the third dose, 78%, 67%, 43%, and 31% of recipients in the 90-, 45-, 15-, and 7.5-µg-dose groups had a MN GMT ≥ 1:40, respectively. Five months later, MN GMTs were significantly greater than those after the second dose. (Trial registration: Clinical Trials.gov identifier NCT00240968.) [ABSTRACT FROM AUTHOR]

The article presents a randomized controlled trial that examined the safety, immunogenicity, and efficacy of a trivalent influenza virus hemagglutinin vaccine that was produced in insect cells using recombinant baculoviruses. The authors of the study found that the vaccine was safe and immunogenic in a healthy population of adults. They also found preliminary evidence that showed the vaccine had a protective effect against a drifted influenza A virus. The inclusion of a neuraminidase component was not required for the protective effect.

Seasonal influenza continues to have a huge annual impact in the United States, accounting for tens of millions of illnesses, hundreds of thousands of excess hospitalizations, and tens of thousands of excess deaths. Vaccination remains the mainstay for the prevention of influenza. In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine and live attenuated influenza vaccine. Both are safe and effective in the populations for which they are approved for use. Children, adults <65 years of age, and the elderly all receive substantial health benefits from vaccination. In addition, vaccination appears to be cost-effective, if not cost saving, across the age spectrum. Despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain too low across all age groups. Important issues to be addressed include improving vaccine delivery to current and expanded target groups, ensuring timely availability of adequate vaccine supply, and development of even more effective vaccines. Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. The use of existing technologies for influenza vaccine production would be the most straightforward approach, because these technologies are commercially available and licensing would be relatively simple. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines. Preliminary results have suggested that, for some pandemic antigens, particularly H5, subvirion inactivated vaccines are poorly immunogenic, for reasons that are not clear. Data from evaluation of live pandemic vaccines are pending. Second-generation approaches designed to provide improved immune responses at lower doses have focused on adjuvants such as alum and MF59, which are currently licensed for influenza or other vaccines. Additional experimental approaches are required to achieve the ultimate goal for seasonal and pandemic influenza prevention—namely, the ability to generate broadly cross-reactive and durable protection in humans. [ABSTRACT FROM AUTHOR]

Background. Influenza-virus hemagglutinin (HA) protein expressed in insect cells by recombinant baculovirus is a candidate influenza vaccine. Methods. In a randomized, double-blind trial conducted in 399 adults ⩾65 years of age, the efficacy of trivalent inactivated influenza vaccine (TIV) licensed for intramuscular injection was compared with that of trivalent baculovirus-expressed HA vaccine administered at doses of 15 µg, 45 µg, or 135 µg of each HA. Results. Compared with TIV, baculovirus-expressed HA vaccine was safe and induced better serum antibody responses to the H3 component when administered at doses of 45 µg or 135 µg of each HA. Conclusions. Baculovirus-expressed HA is a safe and immunogenic influenza vaccine in elderly adults. [ABSTRACT FROM AUTHOR]

Reports on a randomized controlled trial to evaluate the efficacy and safety of the oral neuraminidase inhibitor oseltamivir in the treatment of naturally acquired influenza infection. Design; Setting; Participants; Interventions; Main outcome measures; Results; Conclusions.

Context: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered.Objective: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans.Design: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997.Setting: Individual hotel rooms; 2 large US university medical schools.Participants: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8).Interventions: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days.Main Outcome Measures: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers.Results: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food.Conclusions: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza. [ABSTRACT FROM AUTHOR]

Background: Although influenza vaccination is recommended in persons infected with HIV-1, its efficacy is unknown.Objective: To assess the immunogenicity, efficacy, and risks associated with influenza vaccination in persons infected with HIV-1.Design: Randomized, double-blind, placebo-controlled trial.Setting: Outpatient military clinic.Patients: 102 patients with HIV-1 infection.Intervention: Influenza vaccine (n = 55) or saline placebo (n = 47).Measurements: Influenza antibody titers, CD4+ cell counts, and plasma HIV-1 RNA levels at baseline, 1 month after immunization, and 3 months after immunization; viral cultures from persons presenting with respiratory illness; and respiratory symptom interview.Results: Twenty-three placebo recipients (49%) and 16 vaccine recipients (29%) reported respiratory symptoms (P = 0.04). Ten placebo recipients but no vaccine recipients had laboratory-confirmed symptomatic influenza (P < 0.001) (protective efficacy, 100% [95% CI, 73% to 100%]). No effect on plasma HIV-1 RNA levels or CD4+ cell counts was noted.Conclusion: Influenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count. [ABSTRACT FROM AUTHOR]

Evaluates whether intranasal administration of the sialic acid analog 4-guanidino-Neu5Ac2en (GG167), an inhibitor of influenza virus neuraminidase, was effective and safe in either preventing or treating experimental human influenza. Evaluation of the therapeutic effects of GG167; Frequencies of local nasal intolerance.

Objective: To evaluate the efficacy of adding intranasal live attenuated cold-adapted influenza A vaccine to inactivated influenza vaccine to prevent influenza A in elderly residents of long-term-care institutions.Design: Randomized, double-blind, placebo-controlled study conducted over 3 years.Setting: Three large nursing homes.Participants: A total of 523 residents of nursing homes (mean age, 84.2 years).Interventions: All participants received trivalent inactivated influenza vaccine parenterally and were randomly assigned to receive either live attenuated influenza A (H3N2) virus vaccine or placebo intranasally.Measurements: Laboratory-documented influenza A was defined as a respiratory illness plus isolation of influenza A virus from nasal secretions, significant serologic response, or both. Participants were considered to have been exposed to influenza A if they resided in an institution in which cases of influenza A were documented. Outbreak-associated illnesses were defined as those occurring between the first and last isolation of influenza virus from within the institution, +/- 3 days.Results: Participants who received intranasal vaccine and were subsequently exposed to influenza A had significantly lower rates of laboratory-documented influenza A (9 of 162 vaccine recipients compared with 24 of 169 placebo recipients; vaccine protective efficacy, 60.6%; 95% CI, 18% to 82%), outbreak-associated respiratory illnesses (13 of 162 vaccine recipients compared with 34 of 169 placebo recipients; vaccine protective efficacy, 56.8%; CI 23% to 76%), and outbreak-associated influenza-like illnesses (6 of 162 vaccine recipients compared with 18 of 169 placebo recipients; vaccine protective efficacy, 65.0%; CI 17% to 86%).Conclusions: Intranasal immunization with live attenuated influenza A virus vaccine provided additional protection against influenza A when added to parenteral trivalent inactivated influenza vaccine among elderly nursing home residents. [ABSTRACT FROM AUTHOR]

The author discusses the assessment of influenza vaccine effectiveness during the 2010–2011 influenza season, using a nonrandomized, prospectively followed cohort analysis. It reports two findings which includes the rate of polymerase chain reaction–documented influenza illness was not substantially different and influenza vaccination in a previous season may have impacted the effectiveness of the vaccine in the current season.

The author emphasizes the need to expand the options for addressing pandemic influenza. He cites the limitation of vaccination in preventing pandemic influenza. He discuss two reports that offer information on pandemic influenza prevention, including a randomized clinical trial involving patients who received influenza A/Shanghai/2/13 (H7N9) inactivated virus vaccine intramuscularly. He also cites the need to do further research on hemagglutinin inhibition and neutralizing antibody.

Despite the benefits of yearly influenza vaccination, accumulating evidence suggests that diminished vaccine efficacy may be related to repeated vaccination. Although studied at the level of B-cell responses, CD4 T-cell responses have not yet been examined. In this study, we analyze CD4 T-cell responses to influenza vaccination in subjects who differ in their vaccine history. We find a striking disparity in their responses, with previously vaccinated subjects exhibiting significantly blunted CD4 T-cell responses and diminished antibody responses. These results suggest that limiting CD4 T-cell help mteaserrlie the diminished or altered antibody responses in repeatedly vaccinated subjects. [ABSTRACT FROM AUTHOR]

We describe a statistical approach to compare absolute antibody concentrations, both within and across subjects, derived from a multidimensional measurement of IgG binding to the influenza surface receptor hemagglutinin (HA). This approach addresses a fundamental problem in the field of vaccine immunology: how to accurately compare the levels of antibodies against multiple influenza strains. The mPlex-Flu assay can simultaneously measure the concentration of IgG antibodies against up to 50 influenza strains with only ≤10  μl of serum. It yields mean fluorescence intensity (MFI) over a 4-log range with low inter- and intrasample variability. While comparison of IgG binding to a single HA between subjects is straightforward, variations in binding behavior across influenza strains, coupled with reagent variations, make quantifying and comparing binding between multiple HA subtypes within subjects challenging. In this paper, we first treat such HA variations as an independent antigen and calculate each subtype antibody concentration using its own standard curve, normalizing variations in HA binding. We applied this method to the analyses of data from an H5 influenza clinical vaccine study. The results demonstrated that there are differences in coefficient estimates and in results of "comparing groups" between those with versus those without consideration of subtype antibody variations. Then, we used simulation studies to show the importance of taking the subtype antibody variations into account in HA strain antibody data analysis. Using a common standard curve for all subtype antibodies resulted in both inflated type I error and lowered specificity when comparing different treatment groups. Our results suggest that using individual standard curves for each influenza HA strain, and independently calculating anti-HA IgG concentrations, allows for adjustment of influenza HA subtype variations in treatment group comparisons in clinical vaccine studies. This method facilitates the direct comparison of serum anti-HA IgG concentrations against different influenza HA subtypes for multiplex assays. [ABSTRACT FROM AUTHOR]

The article comments on the recent public health threat of avian (H5N1) influenza virus infections that have been detected in Thailand, resulting in 138 deaths. The author shares that our resources to combat such infections are limited but provides news of the beneficial effects of the passive immunotherapy during the 1918 Spanish influenza pneumonia. He stresses the importance of distinguishing between disease prevention and treatment of active disease.

Abstract: Concerns over migratory bison (Bison bison) at Yellowstone National Park transmitting brucellosis (Brucella abortus) to cattle herds on adjacent lands led to proposals for bison vaccination. We developed an individual-based model to evaluate how brucellosis infection might respond under alternate vaccination strategies, including: (1) vaccination of female calves and yearlings captured at the park boundary when bison move outside the primary conservation area; (2) combining boundary vaccination with the remote delivery of vaccine to female calves and yearlings distributed throughout the park; and (3) vaccinating all female bison (including adults) during boundary capture and throughout the park using remote delivery of vaccine. Simulations suggested Alternative 3 would be most effective, with brucellosis seroprevalence decreasing by 66% (from 0.47 to 0.16) over a 30-year period resulting from 29% of the population receiving protection through vaccination. Under this alternative, bison would receive multiple vaccinations that extend the duration of vaccine protection and defend against recurring infection in latently infected animals. The initial decrease in population seroprevalence will likely be slow due to high initial seroprevalence (40–60%), long-lived antibodies, and the culling of some vaccinated bison that were subsequently exposed to field strain Brucella and reacted positively on serologic tests. Vaccination is unlikely to eradicate B. abortus from Yellowstone bison, but could be an effective tool for reducing the level of infection. Our approach and findings have applicability world-wide for managers dealing with intractable wildlife diseases that cross wildlife–livestock and wildlife–human interfaces and affect public health or economic well-being. [ABSTRACT FROM AUTHOR]

Background: Influenza A (H5N1) viruses could cause a severe worldwide epidemic, with high attack rates, large numbers of deaths and hospitalizations, and wide disruption. Effective vaccines against these viruses in humans are urgently needed. Methods: We conducted a multicenter, double-blind two-stage study involving 451 healthy adults 18 to 64 years of age who were randomly assigned in a 2:2:2:2:1 ratio to receive two intramuscular doses of a subvirion influenza A (H5N1) vaccine of 90, 45, 15, or 7.5 μg of hemagglutinin antigen or placebo. The subjects were followed for the safety analysis for 56 days. Serum samples obtained before each vaccination and again 28 days after the second vaccination were tested for H5 antibody by microneutralization and hemagglutination inhibition. Results: Mild pain at the injection site was the most common adverse event for all doses of vaccine. The frequency of a serum antibody response was highest among subjects receiving doses of 45 μg or 90 μg. Among those who received two doses of 90 μg, neutralization antibody titers reached 1:40 or greater in 54 percent, and hemagglutination-inhibition titers reached 1:40 or greater in 58 percent. Neutralization titers of 1:40 or greater were seen in 43 percent, 22 percent, and 9 percent of the subjects receiving two doses of 45, 15, and 7.5 μg, respectively. No responses were seen in placebo recipients. Conclusions: A two-dose regimen of 90 μg of subvirion influenza A (H5N1) vaccine does not cause severe side effects and, in the majority of recipients, generates neutralizing antibody responses typically associated with protection against influenza. A conventional subvirion H5 influenza vaccine may be effective in preventing influenza A (H5N1) disease in humans. (ClinicalTrials.gov number, NCT00115986.) N Engl J Med 2006;354:1343-51. [ABSTRACT FROM AUTHOR]

CD4 T-cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B-cell production of isotype-switched, high-affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5 , a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein ( NP) or haemagglutinin ( HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history. [ABSTRACT FROM AUTHOR]

Abstract: Substantial H5 influenza HA directed immunity is elicited after vaccination of human subjects who had been previously immunized with a drifted H5 HA variant. We sought to investigate the characteristics of H5 HA specific immune responses in more depth by developing an animal model of H5 HA vaccination using drift variants of recombinant H5 HA proteins. HA proteins derived from influenzas A/Vietnam/1203/04 (Clade 1) and A/Indonesia/05/05 (Clade 2.1) were chosen. The sequence of vaccination consisted of two doses of homologous protein, followed by one additional dose of the homologous or heterologous, drifted HA protein. Each dose of HA was combined with CpG as an adjuvant and was injected subcutaneously. All the animals exhibited a serum IgG antibody response that cross-reacted with both HAs in an ELISA. However, those animals that received the drifted variant exhibited higher reactivity to the heterologous HA. Competitive ELISA of serum from drift-variant recipients showed evidence of antibody focusing towards the drifted HA, suggesting modification of the response towards improved cross-reactivity, though development of neutralizing antibodies was limited. Nevertheless, animals were protected against live-virus challenge, and passive transfer of serum was sufficient to confer protection to otherwise naïve mice, indicating that both neutralizing and non-neutralizing antibodies offer some degree of protection. These findings suggest that pre-vaccination against H5 influenza has the potential to prime immunity against emerging drifted H5 strains, and could also lower the dose requirements of vaccination in the event of a pandemic. [Copyright &y& Elsevier]

Background. Because classic pneumococcal serotyping methods cannot distinguish between serotypes 6A and 6C, the effects of pneumococcal vaccines against serotype 6C are unknown. Pneumococcal vaccines contain serotype 6B but not serotypes 6A and 6C. Methods. We used a phagocytic killing assay to estimate the immunogenicity of the 7-valent conjugate vaccine (PCV7) in children and the 23-valent polysaccharide vaccine (PPV23) in adults against serotypes 6A and 6C. We evaluated trends in invasive pneumococcal disease (IPD) caused by serotypes 6A and 6C in the United States, using active surveillance. Results. Serum specimens from PCV7-immunized children had median opsonization indices of 150 and <20 for serotypes 6A and 6C, respectively. Similarly, only 52% of adults (25 of 48) vaccinated with PPV23 showed opsonic indices of >20 against serotype 6C. During 1999-2006, the incidence of serotype 6A IPD decreased by 91% (from 4.9 to 0.46 cases per 100,000 persons; P < .05) among individuals aged <5 years and by 58% (from 0.86 to 0.36 cases per 100,000 persons; P < .05) among those aged ⩾5 years. Although the incidence of 6C IPD showed no consistent trend (range, 0-0.6 cases per 100,000 persons) among individuals aged <5 years, it increased from 0.25 to 0.62 cases per 100,000 persons (P < .05) among those aged ⩾5 years. Conclusions. PCV7 introduction has led to reductions in serotype 6A IPD but not serotype 6C IPD in the United States. [ABSTRACT FROM AUTHOR]

Background. Dose-sparing strategies are being explored for vaccines against pandemic influenza. We evaluated the dose-sparing potential of aluminum hydroxide (AlOH) adjuvant. Methods. A total of 600 healthy subjects (age, 18-49 years) were randomized to receive 2 vaccinations 1 month apart with subvirion inactivated influenza A/H5N1 vaccine containing 7.5, 15, or 45 μg of hemagglutinin (HA), with or without 600 μg of aluminum hydroxide (AlOH), or 3.75 μg of HA, with or without 300 μg of AlOH. Serum specimens were obtained for antibody assays before and 1 month after each vaccination. Results. All formulations were safe. Injection site discomfort was more frequent in groups given vaccines with AlOH. Dose-related increases in antibody responses were noted after both vaccinations (P < .001): geometric mean titers of hemagglutination inhibition antibody in vaccines with and without AlOH, respectively, were 5.4 and 5.4 for subjects who received 3.75 μg of HA, 7.7 and 5.3 for those who received 7.5 μg of HA, 8.1 and 8.5 for those who received 15 μg of HA, and 14.8 and 12 for those who received 45 μg of HA. A ⩾4-fold increase in titer was observed in 2% and 2% of subjects who received 3.75 μg of HA with or without AlOH, respectively; in 14% and 0% who received 7 μg of HA; in 14% and 13% who received 15 μg of HA; and in 33% and 25% who received 45 μg of HA. Addition of AlOH enhanced responses only for subjects who received 7.5 μg of HA, but responses in subjects who received 7.5 μg of HA without AlOH were unexpectedly low. Conclusion. Overall, a meaningful beneficial effect of AlOH adjuvant was not observed. Trial registration. ClinicalTrials.gov identifier: NCT00296634. [ABSTRACT FROM AUTHOR]

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults. [ABSTRACT FROM AUTHOR]

Background: The Centers of Excellence for Influenza Research and Surveillance (CEIRS) network, funded by the US National Institutes of Health, has been operational since 2007 and is tasked with conducting research to improve understanding of influenza viruses. Recently, CEIRS developed an Influenza Response Plan (IRP) to improve science preparedness for the network. Methods: Development of the IRP involved a collaborative process between project staff, CEIRS center directors or their designees, and NIAID CEIRS leadership (referred to as the Pandemic Planning Advisory Committee [PPAC]). Project staff identified and summarized the response capabilities of each center and then worked with the PPAC to identify and rank research priorities for an emergency response using a modified Delphi method. Results: Key elements of the response plan include tables of response capabilities for each CEIRS center, a framework that outlines and ranks research priorities for CEIRS during an emergency situation, and an operational strategy for executing the research priorities. Conclusions: The CEIRS IRP highlights the importance of enhancing science preparedness in advance of an influenza pandemic or other influenza‐related zoonotic incident to ensure that research can be carried out expeditiously and effectively in emergency situations and to improve global health security. [ABSTRACT FROM AUTHOR]

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned. Author summary: The 2009 influenza pandemic was a stark reminder that ongoing vigilance is critical to protect the public from an influenza pandemic. The continual evolution of influenza viruses and emergence from animal reservoirs, leads to the need to quickly identify strains that pose a public health risk. In these studies, members of the National Institutes of Allergy and Infectious Diseases (NIAID) Centers for Excellence in Influenza Research and Surveillance (CEIRS) network worked together to demonstrate that the emerging canine H3 influenza viruses posed a low risk to public health and identified several therapeutic options in the event of an emergence. In addition to providing important new basic research, many lessons were learned that may be important in dealing with any emerging disease outbreak. [ABSTRACT FROM AUTHOR]

Joining polysaccharide antigens to protein increases immunogenicity in infants. In older adults, using conjugation to protein carriers to improve the immune response to pneumococcal polysaccharide vaccine has thus far proved disappointing. Low immunity to the carrier protein in the elderly may explain the failure of conjugated vaccines to elicit a T-cell-dependent response. We immunized 49 older adults (ages 60-78) and 50 younger adults (ages 18-45) with either 23-valent pneumococcal polysaccharide (PS) vaccine or 5-valent CRM[sub 197]-conjugated pneumococcal oligosaccharide. Sera obtained before and after vaccination were analyzed for antibody to pneumococcal serotypes 14 and 6B and diphtheria toxin by ELISA. Baseline diphtheria toxin antibody level was lower in older adults than in younger adults (0.31 and 0.88 IU/ml, respectively; p < 0.0001). Adults with higher diphtheria antibody level had a higher antibody level to PS type 6B after vaccination than those with lower diphtheria antibody level (9.9 vs. 3.5 m µg/ml, respectively; p = 0.01). Antibody level to PS type 14 was higher, but differed by baseline anti-diphtheria antibody level only when the older group was evaluated alone. Low levels of antibody to diphtheria protein may explain some of the lower responses to conjugate pneumococcal vaccine in older adults. [ABSTRACT FROM AUTHOR]

Vaccination is the best measure of protection against influenza virus infection. Vaccine-induced antibody responses target mainly the hemagglutinin (HA) surface glycoprotein, composed of the head and the stalk domains. Recently two novel vaccine platforms have been developed for seasonal influenza vaccination: a recombinant HA vaccine produced in insect cells (Flublok) and Flucelvax, prepared from virions produced in mammalian cells. In order to compare the fine specificity of the antibodies induced by these two novel vaccine platforms, we characterized 42 Flublok-induced monoclonal antibodies (MAbs) and 38 Flucelvax-induced MAbs for avidity, cross-reactivity, and any selectivity toward the head versus the stalk domain. These studies revealed that Flublok induced a greater proportion of MAbs targeting epitopes near the receptor-binding domain on HA head (hemagglutinin inhibition-positive MAbs) than Flucelvax, while the two vaccines induced similar low frequencies of stalk-reactive MAbs. Finally, mice immunized with Flublok and Flucelvax also induced similar frequencies of stalk-reactive antibodysecreting cells, showing that HA head immunodominance is independent of immune memory bias. Collectively, our results suggest that these vaccine formulations are similarly immunogenic but differ in the preferences of the elicited antibodies toward the receptor-binding domain on the HA head. [ABSTRACT FROM AUTHOR]

The current gold standard for measuring antibody-based immunity to influenza viruses relies on the hemagglutinin inhibition assay (HAI), an 80-year-old technology, and the microneutralization assay (MN). Both assays use serial dilution to provide a discrete, ranked readout of 8–14 categorical titer values for each sample. In contrast to other methods of measuring vaccine antibody levels that produce a continuous readout (i.e., mPLEX-Flu and ELISA), titering methods introduce imprecision and increase false discovery rates (FDR). In this paper, we assess the degree of such statistical errors, first with simulation studies comparing continuous data with titer data in influenza vaccine study group comparison analyses and then by analyzing actual sample data from an influenza vaccine trial. Our results show the superiority of using continuous, rather than discrete, readout assays. Compared to continuous readout assays, titering assays have a lower statistical precision and a higher FDR. The results suggested that traditional titering assays could lead to increased Type-II errors in the comparison of different therapeutic arms of an influenza vaccine trial. These statistical issues are related to the mathematical nature of titer-based assays, which we examine in detail in the simulation studies. Continuous readout assays are free of this issue, and thus it is possible that comparisons of study groups could provide different results with these two methods as we have shown in our case study. [ABSTRACT FROM AUTHOR]

Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus. [ABSTRACT FROM AUTHOR]

Background: Influenza A pandemics cause significant mortality and morbidity. H2N2 viruses have caused a prior pandemic, and are circulating in avian reservoirs. The age-related frequency of current population immunity to H2 viruses was evaluated.Methods: Hemagglutinin inhibition (HAI) assays against historical human and recent avian influenza A(H2N2) viruses were performed across age groups in Rochester, New York, and Hong Kong, China. The impact of existing cross-reactive HAI immunity on the effective reproduction number was modeled.Results: One hundred fifty individual sera from Rochester and 295 from Hong Kong were included. Eighty-five percent of patients born in Rochester and Hong Kong before 1968 had HAI titers ≥1:40 against A/Singapore/1/57, and >50% had titers ≥1:40 against A/Berkeley/1/68. The frequency of titers ≥1:40 to avian H2N2 A/mallard/England/727/06 and A/mallard/Netherlands/14/07 in subjects born before 1957 was 62% and 24%, respectively. There were no H2 HAI titers >1:40 in individuals born after 1968. These levels of seroprevalence reduce the initial reproduction number of A/Singapore/1/1957 or A/Berkeley/1/68 by 15%-20%. A basic reproduction number (R0) of the emerging transmissible virus <1.2 predicts a preventable pandemic.Conclusions: Population immunity to H2 viruses is insufficient to block epidemic spread of H2 virus. An H2N2 pandemic would have lower impact in those born before 1968. [ABSTRACT FROM AUTHOR]