Effect of Aluminum Hydroxide Adjuvant on the Immunogenicity of the 2009 Pandemic Influenza A/H1N1 Vaccine:Multi-level Modeling of Data with Repeated Measures

Objective To evaluate the effect of the aluminum hydroxide （Al-OH） adjuvant on the 2009 pandemic influenza A/H1N1 （pH1N1） vaccine. Methods In a multicenter, double-blind, randomized, placebo-controlled trial, participants received two doses of split-virion formulation containing 15 ug hemagglutinin antigen, with or without aluminum hydroxide （N-OH）. We classified the participants into six age categories （〉61 years, 41-60 years, 19-40 years, 13-18 years, 8-12 years, and 3-7 years） and obtained four blood samples from each participant on days 0, 21, 35, and 42 following the first dose of immunization. We assessed vaccine immunogenicity by measuring the geometric mean titer （GMT） of hemagglutination inhibiting antibody. We used a two-level model to evaluate the fixed effect of aluminum Al-OH and other factors, accounting for repeated measures. Results The predictions of repeated measurement on GMTs of formulations with or without Al-OH, were 80.35 and 112.72, respectively. Al-OH significantly reduced immunogenicity after controlling for time post immunization, age-group and gender. Conclusion The Al-OH adjuvant does not increase but actually reduces the immunogenicity of the split-virion pH1N1 vaccine.

Immunogenic and Protective Properties of the First Kazakhstan Vaccine against Pandemic Influenza А(Н1N1) pdm09 in Ferrets

This paper presents the results of a pre-clinical study of the immunogenicity and efficacy of an egg-derived, inactivated, whole-virion adjuvanted vaccine （Refluvac） on ferret models. For this purpose, groups of eight ferrets （6 to 7 months old） were injected with 0.5 mL of vaccine specimens containing 3.75, 7.5 or 15.0 μg of virus hemagglutinin. Administration was intramuscular and given either as a single dose or as two doses 14 days apart. All vaccine specimens manifested immunogenicity in ferrets for single （HI titer, from 51 ± 7 to 160 ± 23） and double （HI titer, from 697± 120 to 829 ± 117） administrations. To assess the protective effects of the vaccine, ferrets from the vaccinated and control groups were infected intranasally with pandemic virus A/California/7/09 （H1N1） pdm09 at a dose of 106 106/0.5 mL. Fourteen days post-infection, the ferrets inoculated with single or double vaccines containing 3.75, 7.5 or 15.0 ~g of hemagglutinin per dose showed no signs of influenza infection, weight loss, or body temperature rise, and no premature deaths occurred. The number of vaccinated ferrets shedding the virus via the upper airway, as well as the amount of virus shed after infection, was significantly reduced in comparison with animals from the control group. Based on our results, we suggest that a single vaccination at a dose of 3.75 or 7.5 μg hemagglutinin be used for Phase I clinical trials.

The emergence of pandemic influenza viruses

Pandemic influenza has posed an increasing threat to public health worldwide in the last decade.In the 20th century,three human pandemic influenza outbreaks occurred in 1918,1957 and 1968,causing significant mortality.A number of hypotheses have been proposed for the emergence and development of pandemic viruses,including direct introduction into humans from an avian origin and reassortment between avian and previously circulating human viruses,either directly in humans or via an intermediate mammalian host.However,the evolutionary history of the pandemic viruses has been controversial,largely due to the lack of background genetic information and rigorous phylogenetic analyses.The pandemic that emerged in early April 2009 in North America provides a unique opportunity to investigate its emergence and development both in human and animal aspects.Recent genetic analyses of data accumulated through long-term influenza surveillance provided insights into the emergence of this novel pandemic virus.In this review,we summarise the recent literature that describes the evolutionary pathway of the pandemic viruses.We also discuss the implications of these findings on the early detection and control of future pandemics.

Efficacy of seasonal pandemic influenza hemagglutinin DNA vaccines delivered by electroporation against aseasonal H1N1 virus challenge in mice

Prophylactic DNA vaccines against the influenza virus are promising alternatives to conventional vaccines. In this study, we generated two candidate gene-based influenza vaccines encoding either the seasonal or pandemic hemagglutinin antigen （HA） from the strains A/New Caledonia/20/99 （HIN1） （pV1AS） and A/Califorrtia/04/2009 （H1N1） （pVEH1）, respectively. After verifying antigen expression, the immunogenicity of the vaccines delivered intramuscularly with electroporation was tested in a mouse model. Sera of immunized animals were tested in hemagglutination inhibition assays and by ELISA for the presence of HA-specific antibodies. HA-specific T-cells were also measured in IFN-γ ELISpot assays. The protective efficacy of the candidate influenza vaccines was evaluated by measuring mortality rates and body weight after a challenge with 100 LD50 of mouse-adapted A/New Caledonia/20/99 （H1N1）. Mice immunized with either one of the two vaccines showed significantly higher T cell and humoral immune responses （P〈0.05） than the pVAX1 control group. Additionally, the pV1A5 vaccine effec- tively protected the mice against a lethal homologous mouse-adapted virus challenge with a survival rate of 100% compared with a 40% survival rate in the pVEH1 vaccinated group （P〈0.05）. Our study indicates that the seasonal influenza DNA vac- cine completely protects against the homologous A/New Caledonia/20/99 virus （H1N1）, while the pandemic influenza DNA vaccine only partially protects against this virus.

INTEGRATING COMPLEX SYSTEM DYNAMICS OF PANDEMIC INFLUENZA WITH A MULTI-CRITERIA DECISION MAKING MODEL FOR EVALUATING PUBLIC HEALTH STRATEGIES

Recent developments in computational sciences and computer modeling have allowed emergency preparedness exercises to include simulation models as supporting tools. These simulation models are generally built for predicting temporal and geographic patterns of disease spread. However sole use of simulation models in exercise design falls short in terms of incorporating policy decision makers＇ preferences into decision-making processes. In this paper, a general framework for exercising public health preparedness plans with a decision support system is presented to integrate estimation of key epidemiological parameters with a system dynamics model of an outbreak. A multi-criteria decision making framework, an Analytical Hierarchy Process model, is then developed and integrated with the simulation model to help public health policy makers prioritize their response goals and evaluate mitigation strategies in a table-top exercise environment.

Forecast the Influenza Pandemic Using Machine Learning

Forecasting future outbreaks can help in minimizing their spread.Influenza is a disease primarily found in animals but transferred to humans through pigs.In 1918,influenza became a pandemic and spread rapidly all over the world becoming the cause behind killing one-third of the human population and killing one-fourth of the pig population.Afterwards,that influenza became a pandemic several times on a local and global levels.In 2009,influenza‘A’subtype H1N1 again took many human lives.The disease spread like in a pandemic quickly.This paper proposes a forecasting modeling system for the influenza pandemic using a feed-forward propagation neural network(MSDII-FFNN).This model helps us predict the outbreak,and determines which type of influenza becomes a pandemic,as well as which geographical area is infected.Data collection for the model is done by using IoT devices.This model is divided into 2 phases:The training phase and the validation phase,both being connected through the cloud.In the training phase,the model is trained using FFNN and is updated on the cloud.In the validation phase,whenever the input is submitted through the IoT devices,the system model is updated through the cloud and predicts the pandemic alert.In our dataset,the data is divided into an 85%training ratio and a 15%validation ratio.By applying the proposed model to our dataset,the predicted output precision is 90%.

Association of swine influenza H1N1 pandemic virus(SIV-H1N1p) with porcine respiratory disease complex in sows from commercial pig farms in Colombia

Porcine respiratory disease complex （PRDC） is a serious health problem that mainly affects growing and finishing pigs. PRDC is caused by a combination of viral and bacterial agents, such as porcine reproductive and respiratory syndrome virus （PRRSV）, swine influenza virus （SIV）, Mycoplasma hyopneumoniae （Myh）, Actinobacillus pleuropneumoniae （APP）, Pasteurella multocida and Porcine circovirus 2 （PCV2）. To characterize the specific role of swine influenza virus in PRDC presentation in Colombia, 11 farms from three major production regions in Colombia were examined in this study. Nasal swabs, bronchial lavage and lung tissue samples were obtained from animals displaying symptoms compatible with SIV. Isolation of SIV was performed in 9-day embryonated chicken eggs or Madin-Darby Canine Kidney （MDCK） cells. Positive isolates, identified via the hemagglutination inhibition test, were further analyzed using PCR. Overall, 7 of the 11 farms were positive for SIV. Notably, sequencing of the gene encoding the hemagglutinin （HA） protein led to grouping of strains into circulating viruses identified during the human outbreak of 2009, classified as pandemic H1N1-2009. Serum samples from 198 gilts and multiparous sows between 2008 and 2009 were obtained to determine antibody presence of APP, Myh, PCV2 and PRRSV in both SIV-H1Nlp-negative and -positive farms, but higher levels were recorded for SIV- HI Nlp-positive farms. Odds ratio （OR） and P values revealed statistically significant differences （p〈0.05） in PRDC presentation in gilts and multiparous sows of farms positive for SIV-HINlp. Our findings indicate that positive farms have increased risk of PRDC presentation, in particular, PCV2, APP and Myh.

The Optimal Allocation of Investment between Antivirals and Vaccines for Influenza Pandemic Preparedness Planning

Objectives To investigate that given a fixed amount of financial resources,what is the optimal combination of vaccine and antiviral stockpiles in terms of minimizing the attack rate.Methods Mathematic modeling was used to simulate the dynamics that with fixed influenza pandemic budget.Different budget conditions were observed if the combination changed.Framework between vaccines and antivirals was introduced by taking into account the uncertainty in vaccine and antiviral efficacy.Results Given a fixed budget,different budget allocations between vaccines and antivirals stockpile gave different attack rates.When the price of vaccine was lower than or similar with the antivirals,the attack rate increased with increasing investment in antiviral.But if the price of the vaccine was higher than the antivirals,the attack rate may not decrease with increasing investment in vaccine.Fixed the vaccine effectiveness,higher effectiveness of antiviral got a lower attack rate.When both antiviral and vaccine were with 50%probability of effectiveness,the attack rate changed by antiviral stockpile with a same pattern as they were with 100%efficacy probability,even it has a higher attack rate.Conclusions Assume the antivirals have 100%probability to be effective,budget was limited to a fix number,then in any event,population should stockpile a small amount of antivirals such that if the post-vaccination reproductive number turns out to be near 1,the additional intervention may further reduce the reproductive number to <1 and prevent the epidemic.Under the fixed budget,the price of the vaccines and antivirals will strongly affect the strategy of the stockpile allocation.When the price of vaccine is comparative lower,more investment of vaccine is better for the pandemic control,but if the vaccine price is too high then more investment in antiviral may be better.We found that attack rates and the optimal budget allocation depend on the probability to be effective of vaccine and antivirals.

Risk Perception of Seasonal and Swine Influenza Among University College Students： Does Study Direction Influence Attitudes？

In 2009, Norway faced the global challenge of the influenza pandemic. Risk communication is an important tool within healthy promoting work. In this study the main aim was to explore reflections of students on the risk assessment of season flu and the swine flu in 2009 according to field of study. A cross-sectional questionnaire survey based on 505 students is presented. 42.4% were health subject students, and 57.6% were non-health subject related students. The majority of the students were 20-24 years old. Most of the respondents were not concerned at being infected with the swine flu, and did underestimate the death toll of the common flu. Students were more concerned about the swine flu than the regular season flu. By logistic regression, the odds ratio for taking the swine flu vaccine was greater among students who were concerned （O.R. = 2.5）. During the swine flu pandemic, student trust towards the health authorities was low. Among the students, 74% stated they would consider advice from the health authorities, 37% from their parents and 20% from mass media. Stating risk of getting the common flu was at the medium or great risk level for far less non-health students than for health students, 38.2% versus 55.6%, P = 0.001. The perceived infection risk was likewise higher in the health student group, 52.4% versus 36.2%, P = 0.001. The respondents had little faith in general public vaccination as well as being critical concerning side effects of vaccination. The results from the study indicated that the students would rather follow advice about their personal hygiene than advice to take the swine flu-vaccine.

Global influenza in cold phase of Pacific Decade Oscillation

Based on the study of the cold phase of the Pacific Decade Oscillation, pandemic influenza is related to climate. The relation of low temperature, Pacific Decade Oscillation, strongest earthquake, Influenza, hurricane and E1 Nino is researched in this study. In the cold period of Pacific Decade Oscillation, the strongest earthquake, hurricane with La Ni＇na, Pandemic Influenza with E1 Nino will occur stronger and stronger. From 1950 to 1976, the strongest dust-storm is connected with Pandemic Influenza one by one. So, dust-storm is one of factors to spread pandemic influenza viruses.

The S190R mutation in the hemagglutinin protein of pandemic H1N1 2009 influenza virus increased its pathogenicity in mice

Human influenza viruses preferentially bind to sialic acid-α2,6-galactose (SAα2,6Gal) receptors, which are predominant in human upper respiratory epithelia, whereas avian influenza viruses preferentially bind to SAα2,3Gal receptors. However, variants with amino acid substitutions around the receptor-binding sites of the hemagglutinin (HA) protein can be selected after several passages of human influenza viruses from patients’ respiratory samples in the allantoic cavities of embryonated chicken eggs. In this study, we detected an egg-adapted HA S190R mutation in the pandemic H1N1 virus 2009 (pdmH1N1), and evaluated the effects of this mutation on receptor binding affinity and pathogenicity in mice. Our results revealed that residue 190 is located within the pocket structure of the receptor binding site. The single mutation to arginine at position 190 slightly increased the binding affinity of the virus to the avian receptor and decreased its binding to the long human α2,6-linked sialic acid receptor. Our study demonstrated that the S190R mutation resulted in earlier death and higher weight loss in mice compared with the wild-type virus. Higher viral titers at 1 dpi (days post infection) and diffuse damage at 4 dpi were observed in the lung tissues of mice infected with the mutant virus.

Stigmatization and Scientific Inquiry in the Tracing of the Origin of the 1918 Influenza Pandemic in the United States

The United States was hard hit by the great influenza pandemic of 1918.The national policy of putting the war first,the unprecedented scale of military training,and the worldwide troop movements and engagement created the conditions for the spread of the pandemic and at the same time seriously weakened US preparedness.The unprecedented pandemic threw American society into extreme panic and spawned all kinds of hypotheses about the pandemic’s geographic origin.Some of the press turned scientifically“tracing the flu”into a succession of pejorative geopolitical exonyms,stigmatizing it as“Spanish flu,”“Russian flu,”“German poisoning,”“Chinese plague,”etc.The groundless ascription of a geographic origin to the influenza pandemic was questioned at the time by insightful American medical professionals and even by Chinese medical experts.In the aftermath of the pandemic,tracking its source became a professional issue of pure medical science,with the search for the pathogen of the pandemic becoming a priority.The discovery and genetic sequencing of the 1918 influenza virus by scientists in the US and other countries led to landmark advances in the discovery of the pathogen,so the importance of tracing it back to its place of origin has taken a back seat.Although evidence of the geographic origin of the 1918 influenza pandemic is not conclusive,medical science has developed enough to disprove the ridiculous“geographic tracking”in the US during the pandemic.

Detection and pathogenesis of a novel swine H3N2 influenza virus containing three genes from the 2009 pandemic H1N1 influenza viruses in Korea in 2015

Dear Editor,Influenza A viruses cause pandemics at an interval of approximately 10-40 years,and pigs are regarded as a＂mixing vessel＂because they are easily infected with avian and human influenza viruses（Ito et al.,1998）.According to previous studies,H3N2,H1N2,and H1N1 subtypes o（swine influenza viruses have been detected in Korean pigs （Pascua et al., 2013; Kim et al., 2014; Song et al., 2007）. Moreover, a novel H3N2 influenza virus containing the matrix （34） gene from a 2009 pandemic influenza virus was detected in Korean pigs in 2013 （Pascua et al., 2013）, an H1N2 influenza virus con- taining the internal genes from a 2009 pandemic influ- enza virus was found in Korean pigs in 2014 （Kim et al., 2014）, and an H1N1 influenza virus containing all genes from the classical swine influenza viruses was isolated from Korean pigs in 2007 （Song et al., 2007）.