A biological model for influenza transmission: pandemic planning implications of asymptomatic infection and immunity

Background

The clinical attack rate of influenza is influenced by prior immunity and mixing patterns in the host population, and also by the proportion of infections that are asymptomatic. This complexity makes it difficult to directly estimate R₀ from the attack rate, contributing to uncertainty in epidemiological models to guide pandemic planning. We have modelled multiple wave outbreaks of influenza from different populations to allow for changing immunity and asymptomatic infection and to make inferences about R₀.

Data and Methods

On the island of Tristan da Cunha (TdC), 96% of residents reported illness during an H3N2 outbreak in 1971, compared with only 25% of RAF personnel in military camps during the 1918 H1N1 pandemic. Monte Carlo Markov Chain (MCMC) methods were used to estimate model parameter distributions.

Findings

We estimated that most islanders on TdC were non-immune (susceptible) before the first wave, and that almost all exposures of susceptible persons caused symptoms. The median R₀ of 6.4 (95% credibility interval 3.7–10.7) implied that most islanders were exposed twice, although only a minority became ill in the second wave because of temporary protection following the first wave. In contrast, only 51% of RAF personnel were susceptible before the first wave, and only 38% of exposed susceptibles reported symptoms. R₀ in this population was also lower [2.9 (2.3–4.3)], suggesting reduced viral transmission in a partially immune population.

Interpretation

Our model implies that the RAF population was partially protected before the summer pandemic wave of 1918, arguably because of prior exposure to interpandemic influenza. Without such protection, each symptomatic case of influenza would transmit to between 2 and 10 new cases, with incidence initially doubling every 1–2 days. Containment of a novel virus could be more difficult than hitherto supposed.     

Coinfection can trigger multiple pandemic waves

Sequences of epidemic waves have been observed in past influenza pandemics, such as the Spanish influenza. Possible explanations may be sought either in mechanisms altering the structure of the network of contacts, such as those induced by changes in the rates of movement of people or by public health measures, or in the genetic drift of the influenza virus, since the appearance of new strains can reduce or eliminate herd immunity. The pandemic outbreaks may also be influenced by coinfection with other acute respiratory infections (ARI) that increase transmissibility of influenza virus (by coughing, sneezing, running nose). In fact, some viruses (e.g., Rhinovirus and Adenovirus) have been found to induce “clouds” of bacteria and increase the transmissibility of Staphylococcus aureus. Moreover, Rhinovirus and Adenovirus were detected in patients during past pandemics, and their presence is linked to superspreading events. In this paper, by assuming increased transmissibility in coinfected individuals, we propose and study a model where multiple pandemic waves are triggered by coinfection with ARI. The model agrees well with mortality excess data during the 1918 pandemic influenza, thereby providing indications for potential pandemic mitigation.     

Transmission dynamics of the great influenza pandemic of 1918 in Geneva, Switzerland: Assessing the effects of hypothetical interventions

Recurrent outbreaks of the avian H5N1 influenza virus in Asia represent a constant global pandemic threat. We characterize and evaluate hypothetical public health measures during the 1918 influenza pandemic in the Canton of Geneva, Switzerland. The transmission rate, the recovery rate, the diagnostic rate, the relative infectiousness of asymptomatic cases, and the proportion of clinical cases are estimated through least-squares fitting of the model to epidemic curve data of the cumulative number of hospital notifications. The latent period and the case fatality proportion are taken from published literature. We determine the variance and identifiability of model parameters via a simulation study. Our epidemic model agrees well with the observed epidemic data. We estimate the basic reproductive number for the spring wave R1;=1.49 (95% CI: 1.45-1.53) and the reproductive number for the fall wave R2;=3.75 (95% CI: 3.57-3.93). In addition, we estimate the clinical reporting for these two waves to be 59.7% (95% CI: 55.7-63.7) and 83% (95% CI: 79-87). We surmise that the lower reporting in the first wave can be explained by a lack of initial awareness of the epidemic and the relative higher severity of the symptoms experienced during the fall wave. We found that effective isolation measures in hospital clinics at best would only ensure control with probability 0.87 while reducing the transmission rate by >76.5% guarantees stopping an epidemic.     

Optimal control for pandemic influenza: The role of limited antiviral treatment and isolation

The implementation of optimal control strategies involving antiviral treatment and/or isolation measures can reduce significantly the number of clinical cases of influenza. Pandemic-level control measures must be carefully assessed specially in resource-limited situations. A model for the transmission dynamics of influenza is used to evaluate the impact of isolation and/or antiviral drug delivery measures during an influenza pandemic. Five pre-selected control strategies involving antiviral treatment and isolation are tested under the “unlimited” resource assumption followed by an exploration of the impact of these “optimal” policies when resources are limited in the context of a 1918-type influenza pandemic scenario. The implementation of antiviral treatment at the start of a pandemic tends to reduce the magnitude of epidemic peaks, spreading the maximal impact of an outbreak over an extended window in time. Hence, the controls’ timing and intensity can reduce the pressures placed on the health care infrastructure by a pandemic reducing the stress put on the system during epidemic peaks. The role of isolation strategies is highlighted in this study particularly when access to antiviral resources is limited.     

Age-Specific Mortality During the 1918 Influenza Pandemic: Unravelling the Mystery of High Young Adult Mortality

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889–90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

“The war is over – and I must go” Egon Schiele, 1890–1918.

     

The Possible Impact of Vaccination for Seasonal Influenza on Emergence of Pandemic Influenza via Reassortment

Background

One pathway through which pandemic influenza strains might emerge is reassortment from coinfection of different influenza A viruses. Seasonal influenza vaccines are designed to target the circulating strains, which intuitively decreases the prevalence of coinfection and the chance of pandemic emergence due to reassortment. However, individual-based analyses on 2009 pandemic influenza show that the previous seasonal vaccination may increase the risk of pandemic A(H1N1) pdm09 infection. In view of pandemic influenza preparedness, it is essential to understand the overall effect of seasonal vaccination on pandemic emergence via reassortment.

Methods and Findings

In a previous study we applied a population dynamics approach to investigate the effect of infection-induced cross-immunity on reducing such a pandemic risk. Here the model was extended by incorporating vaccination for seasonal influenza to assess its potential role on the pandemic emergence via reassortment and its effect in protecting humans if a pandemic does emerge. The vaccination is assumed to protect against the target strains but only partially against other strains. We find that a universal seasonal vaccine that provides full-spectrum cross-immunity substantially reduces the opportunity of pandemic emergence. However, our results show that such effectiveness depends on the strength of infection-induced cross-immunity against any novel reassortant strain. If it is weak, the vaccine that induces cross-immunity strongly against non-target resident strains but weakly against novel reassortant strains, can further depress the pandemic emergence; if it is very strong, the same kind of vaccine increases the probability of pandemic emergence.

Conclusions

Two types of vaccines are available: inactivated and live attenuated, only live attenuated vaccines can induce heterosubtypic immunity. Current vaccines are effective in controlling circulating strains; they cannot always help restrain pandemic emergence because of the uncertainty of the oncoming reassortant strains, however. This urges the development of universal vaccines for prevention of pandemic influenza.     

Kinetics of Coinfection with Influenza A Virus and Streptococcus pneumoniae

Secondary bacterial infections are a leading cause of illness and death during epidemic and pandemic influenza. Experimental studies suggest a lethal synergism between influenza and certain bacteria, particularly Streptococcus pneumoniae, but the precise processes involved are unclear. To address the mechanisms and determine the influences of pathogen dose and strain on disease, we infected groups of mice with either the H1N1 subtype influenza A virus A/Puerto Rico/8/34 (PR8) or a version expressing the 1918 PB1-F2 protein (PR8-PB1-F2(1918)), followed seven days later with one of two S. pneumoniae strains, type 2 D39 or type 3 A66.1. We determined that, following bacterial infection, viral titers initially rebound and then decline slowly. Bacterial titers rapidly rise to high levels and remain elevated. We used a kinetic model to explore the coupled interactions and study the dominant controlling mechanisms. We hypothesize that viral titers rebound in the presence of bacteria due to enhanced viral release from infected cells, and that bacterial titers increase due to alveolar macrophage impairment. Dynamics are affected by initial bacterial dose but not by the expression of the influenza 1918 PB1-F2 protein. Our model provides a framework to investigate pathogen interaction during coinfections and to uncover dynamical differences based on inoculum size and strain.     

Complex patterns of human antisera reactivity to novel 2009 H1N1 and historical H1N1 influenza strains

Background

During the 2009 influenza pandemic, individuals over the age of 60 had the lowest incidence of infection with approximately 25% of these people having pre-existing, cross-reactive antibodies to novel 2009 H1N1 influenza isolates. It was proposed that older people had pre-existing antibodies induced by previous 1918-like virus infection(s) that cross-reacted to novel H1N1 strains.

Methodology/Principal Findings

Using antisera collected from a cohort of individuals collected before the second wave of novel H1N1 infections, only a minority of individuals with 1918 influenza specific antibodies also demonstrated hemagglutination-inhibition activity against the novel H1N1 influenza. In this study, we examined human antisera collected from individuals that ranged between the ages of 1 month and 90 years to determine the profile of seropositive influenza immunity to viruses representing H1N1 antigenic eras over the past 100 years. Even though HAI titers to novel 2009 H1N1 and the 1918 H1N1 influenza viruses were positively associated, the association was far from perfect, particularly for the older and younger age groups.

Conclusions/Significance

Therefore, there may be a complex set of immune responses that are retained in people infected with seasonal H1N1 that can contribute to the reduced rates of H1N1 influenza infection in older populations.     

Seroprevalence Following the Second Wave of Pandemic 2009 H1N1 Influenza in Pittsburgh,PA, USA

Background

In April 2009, a new pandemic strain of influenza infected thousands of persons in Mexico and the United States and spread rapidly worldwide. During the ensuing summer months, cases ebbed in the Northern Hemisphere while the Southern Hemisphere experienced a typical influenza season dominated by the novel strain. In the fall, a second wave of pandemic H1N1 swept through the United States, peaking in most parts of the country by mid October and returning to baseline levels by early December. The objective was to determine the seroprevalence of antibodies against the pandemic 2009 H1N1 influenza strain by decade of birth among Pittsburgh-area residents.

Methods and Findings

Anonymous blood samples were obtained from clinical laboratories and categorized by decade of birth from 1920–2009. Using hemagglutination-inhibition assays, approximately 100 samples per decade (n = 846) were tested from blood samples drawn on hospital and clinic patients in mid-November and early December 2009. Age specific seroprevalences against pandemic H1N1 (A/California/7/2009) were measured and compared to seroprevalences against H1N1 strains that had previously circulated in the population in 2007, 1957, and 1918. (A/Brisbane/59/2007, A/Denver/1/1957, and A/South Carolina/1/1918). Stored serum samples from healthy, young adults from 2008 were used as a control group (n = 100). Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10–19 years having the highest seroprevalence (45%), and persons age 70–79 years having the lowest (5%). The baseline seroprevalence among control samples from 18–24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%.

Conclusions

After the peak of the second wave of 2009 H1N1, HAI seroprevalence results suggest that 21% of persons in the Pittsburgh area had become infected and developed immunity. Extrapolating to the entire US population, we estimate that at least 63 million persons became infected in 2009. As was observed among clinical cases, this sero-epidemiological study revealed highest infection rates among school-age children.     

From pandemic to endemic: Spatial-temporal patterns of influenza-like illness incidence in a Swiss canton, 1918–1924

In pandemics, past and present, there is no textbook definition of when a pandemic is over, and how and when exactly a respiratory virus transitions from pandemic to endemic spread. In this paper we have compared the 1918/19 influenza pandemic and the subsequent spread of seasonal flu until 1924. We analysed 14,125 reports of newly stated 32,198 influenza-like illnesses from the Swiss canton of Bern. We analysed the temporal and spatial spread at the level of 497 municipalities, 9 regions, and the entire canton. We calculated incidence rates per 1000 inhabitants of newly registered cases per calendar week. Further, we illustrated the incidences of each municipality for each wave (first wave in summer 1918, second wave in fall/winter 1918/19, the strong later wave in early 1920, as well as the two seasonal waves in 1922 and 1924) on a choropleth map. We performed a spatial hotspot analysis to identify spatial clusters in each wave, using the Gi* statistic. Furthermore, we applied a robust negative binomial regression to estimate the association between selected explanatory variables and incidence on the ecological level. We show that the pandemic transitioned to endemic spread in several waves (including another strong wave in February 1920) with lower incidence and rather local spread until 1924 at least. At the municipality and regional levels, there were different patterns of spread both between pandemic and seasonal waves. In the first pandemic wave in summer 1918 the probability of higher incidence was increased in municipalities with a higher proportion of factories (OR 2.60, 95%CI 1.42–4.96), as well as in municipalities that had access to a railway station (OR 1.50, 95%CI 1.16–1.96). In contrast, the strong fall/winter wave 1918 was very widespread throughout the canton. In general, municipalities at higher altitude showed lower incidence. Our study adds to the sparse literature on incidence in the 1918/19 pandemic and subsequent years. Before Covid-19, the last pandemic that occurred in several waves and then became endemic was the 1918–19 pandemic. Such scenarios from the past can inform pandemic planning and preparedness in future outbreaks.     

MicroRNA Expression and Virulence in Pandemic Influenza Virus-Infected Mice

The worst known H1N1 influenza pandemic in history resulted in more than 20 million deaths in 1918 and 1919. Although the underlying mechanism causing the extreme virulence of the 1918 influenza virus is still obscure, our previous functional genomics analyses revealed a correlation between the lethality of the reconstructed 1918 influenza virus (r1918) in mice and a unique gene expression pattern associated with severe immune responses in the lungs. Lately, microRNAs have emerged as a class of crucial regulators for gene expression. To determine whether differential expression of cellular microRNAs plays a role in the host response to r1918 infection, we compared the lung cellular “microRNAome” of mice infected by r1918 virus with that of mice infected by a nonlethal seasonal influenza virus, A/Texas/36/91. We found that a group of microRNAs, including miR-200a and miR-223, were differentially expressed in response to influenza virus infection and that r1918 and A/Texas/36/91 infection induced distinct microRNA expression profiles. Moreover, we observed significant enrichment in the number of predicted cellular target mRNAs whose expression was inversely correlated with the expression of these microRNAs. Intriguingly, gene ontology analysis revealed that many of these mRNAs play roles in immune response and cell death pathways, which are known to be associated with the extreme virulence of r1918. This is the first demonstration that cellular gene expression patterns in influenza virus-infected mice may be attributed in part to microRNA regulation and that such regulation may be a contributing factor to the extreme virulence of the r1918.H1N1 influenza A viruses continue to pose serious threats to public health, as exemplified by the ongoing 2009 H1N1 influenza pandemic. The 1918-1919 H1N1 influenza pandemic was even deadlier in comparison, causing more than 20 million deaths worldwide. The keys to unlocking the mystery of the extreme virulence of the 1918 virus were provided with the reconstruction of the virus (reconstructed 1918 influenza virus [r1918]) by reverse genetics (37). The lethality of r1918 has since been examined in both mouse and macaque models (17, 18). Unlike the nonlethal infections of some other H1N1 influenza virus strains, such as A/Texas/36/91 (Tx/91) or A/Kawasaki/173/01 (K173), the r1918 causes severe and lethal pulmonary disease. We subsequently conducted functional genomics analyses that revealed that the extreme virulence of r1918 was correlated with atypical expression of immune response-related genes, including massive induction of cellular genes related to inflammatory response and cell death pathways (17, 18). In spite of these findings, the mechanistic basis for these atypical gene expression patterns remains unknown.Cellular gene expression is a complicated process and is subject to regulation by many cellular factors. As a group of newly identified cellular regulators, microRNAs are known to regulate the expression of a large number of targets, mainly cellular genes. Through mRNA degradation or translational repression of their targets, microRNAs regulate a wide range of crucial physiologic and pathological processes. For example, miR-34a acts as a tumor suppressor by inhibiting the expression of sirt1 (40), whereas miR-21 contributes to myocardial disease by inhibiting the expression of spry1 (36). By targeting zeb1/2, the miR-200 family members play roles in maintaining the epithelial phenotype of cancer cells (27). Furthermore, Let-7s regulates the expression of hbl-1, which drives the developmental progression of epidermal stem cells (5). Cellular microRNAs also play critical roles in virus-host interactions. The cellular microRNA miR-122 is an indispensable factor in supporting hepatitis C virus (HCV) replication (16), whereas miR-196 and miR-296 substantially attenuate viral replication through type I interferon (IFN)-associated pathways in liver cells (28). Furthermore, miR-125b and miR-223 directly target human immunodeficiency virus type 1 (HIV-1) mRNA, thereby attenuating viral gene expression in resting CD4⁺ T cells (14), and miR-198 modulates HIV-1 replication indirectly by repressing the expression of ccnt1 (34), a cellular factor necessary for HIV-1 replication. More importantly, viruses may promote their life cycles by modulating the intracellular environment through actively regulating the expression of multiple cellular microRNAs. For example, human T-cell lymphotropic virus type 1 (HTLV-1) modulates the expression of a number of cellular microRNAs in order to control T-cell differentiation (3). Similarly, human cytomegalovirus (HCMV) selectively manipulates the expression of miR-100 and miR-101 to facilitate its own replication (38). In contrast, the involvement of microRNAs during influenza A virus infection or pathogenesis is largely unknown.To determine whether cellular microRNAs play a role in the host response to influenza virus infection, we performed a systematic profiling of cellular microRNAs in lung tissues from mice infected with r1918 or a nonlethal seasonal influenza virus, Tx/91 (17). We identified a group of microRNAs whose expression patterns differentiated the host response to r1918 and Tx/91 infection. We assessed the potential functions of differentially expressed microRNAs by analyzing the predicted target genes whose expression was inversely correlated with the expression of these microRNAs. Our report provides a new perspective on the contribution of microRNAs to the pathogenesis of lethal 1918 influenza virus infection.     

“Pandemic Public Health Paradox”: Time Series Analysis of the 2009/10 Influenza A / H1N1 Epidemiology,Media Attention,Risk Perception and Public Reactions in 5 European Countries

In 2009, influenza A H₁N₁ caused the first pandemic of the 21^st century. Although a vaccine against this influenza subtype was offered before or at the onset of the second epidemic wave that caused most of the fatal cases in Europe, vaccination rates for that season were lower than expected. We propose that the contradiction between high risk of infection and low use of available prevention measures represents a pandemic public health paradox. This research aims for a better understanding of this paradox by exploring the time-dependent interplay among changing influenza epidemiology, media attention, pandemic control measures, risk perception and public health behavior among five European countries (Czech Republic, Denmark, Germany, Spain and the UK). Findings suggest that asynchronicity between media curves and epidemiological curves may potentially explain the pandemic public health paradox; media attention for influenza A H₁N₁ in Europe declined long before the epidemic reached its peak, and public risk perceptions and behaviors may have followed media logic, rather than epidemiological logic.     

Detection of Extensive Cross-Neutralization between Pandemic and Seasonal A/H1N1 Influenza Viruses Using a Pseudotype Neutralization Assay

Background

Cross-immunity between seasonal and pandemic A/H1N1 influenza viruses remains uncertain. In particular, the extent that previous infection or vaccination by seasonal A/H1N1 viruses can elicit protective immunity against pandemic A/H1N1 is unclear.

Methodology/Principal Findings

Neutralizing titers against seasonal A/H1N1 (A/Brisbane/59/2007) and against pandemic A/H1N1 (A/California/04/2009) were measured using an HIV-1-based pseudovirus neutralization assay. Using this highly sensitive assay, we found that a large fraction of subjects who had never been exposed to pandemic A/H1N1 express high levels of pandemic A/H1N1 neutralizing titers. A significant correlation was seen between neutralization of pandemic A/H1N1 and neutralization of a standard seasonal A/H1N1 strain. Significantly higher pandemic A/H1N1 neutralizing titers were measured in subjects who had received vaccination against seasonal influenza in 2008–2009. Higher pandemic neutralizing titers were also measured in subjects over 60 years of age.

Conclusions/Significance

Our findings reveal that the extent of protective cross-immunity between seasonal and pandemic A/H1N1 influenza viruses may be more important than previously estimated. This cross-immunity could provide a possible explanation of the relatively mild profile of the recent influenza pandemic.     

Estimated cumulative incidence of pandemic (H1N1) influenza among pregnant women during the first wave of the 2009 pandemic

Background

Hospitalization and lab confirmed cases of H1N1 have been reported during the first wave of the 2009 pandemic but these are not accurate measures of influenza incidence in the population. We estimated the cumulative incidence of pandemic (H1N1) influenza among pregnant women in the province of Manitoba during the first wave of the 2009 pandemic.

Methods

Two panels of stored frozen serum specimens collected for routine prenatal screening were randomly selected for testing before (March 2009, n = 252) and after (August 2009, n = 296) the first wave of the pandemic. A standard hemagglutination inhibition assay was used to detect the presence of IgG antibodies against the pandemic (H1N1) 2009 virus. The cumulative incidence of pandemic (H1N1) influenza was calculated as the difference between the point prevalence rates in the first and second panels.

Results

Of the specimens collected in March, 7.1% were positive for the IgG antibodies (serum antibody titre ≥ 1:40). The corresponding prevalence was 15.7% among the specimens collected in August. The difference indicated a cumulative incidence of 8.6% (95% confidence interval [CI] 3.2%–13.7%). The rate differed geographically, the highest being in the northern regions (20.8%, 95% CI 7.9%–31.8%), as compared with 4.0% (95% CI 0.0%–11.9%) in Winnipeg and 8.9% (95% CI 0.0%–18.8%) in the rest of the province.

Interpretation

We estimated that the cumulative incidence of pandemic (H1N1) influenza among pregnant women in Manitoba during the first wave of the 2009 pandemic was 8.6%. It was 20.8% in the northern regions of the province.During the first wave of the pandemic (H1N1) 2009, the province of Manitoba was more severely affected than almost any other Canadian province.¹ Pregnant women in particular had higher rates of laboratory-confirmed infection and of severe illness.² However, the number of laboratory-confirmed cases is not an accurate measure of the incidence of influenza in the population. The number and geographic distribution of confirmed cases are influenced by differences in access to medical care, physicians’ practices and other factors.³We estimated the cumulative incidence of pandemic (H1N1) influenza among pregnant women in the province of Manitoba during the first wave of the 2009 pandemic. We did this by measuring the point seroprevalence in random samples of pregnant women presenting for routine prenatal screening before and after the first wave.     

Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice

The 1918 influenza pandemic caused over 40 million deaths worldwide, with 675,000 deaths in the United States alone. Studies in several experimental animal models showed that 1918 influenza virus infection resulted in severe lung pathology associated with dysregulated immune and cell death responses. To determine if reactive oxygen species produced by host inflammatory responses play a central role in promoting severity of lung pathology, we treated 1918 influenza virus-infected mice with the catalytic catalase/superoxide dismutase mimetic, salen–manganese complex EUK-207 beginning 3 days postinfection. Postexposure treatment of mice infected with a lethal dose of the 1918 influenza virus with EUK-207 resulted in significantly increased survival and reduced lung pathology without a reduction in viral titers. In vitro studies also showed that EUK-207 treatment did not affect 1918 influenza viral replication. Immunohistochemical analysis showed a reduction in the detection of the apoptosis marker cleaved caspase-3 and the oxidative stress marker 8-oxo-2′-deoxyguanosine in lungs of EUK-207-treated animals compared to vehicle controls. High-throughput sequencing and RNA expression microarray analysis revealed that treatment resulted in decreased expression of inflammatory response genes and increased lung metabolic and repair responses. These results directly demonstrate that 1918 influenza virus infection leads to an immunopathogenic immune response with excessive inflammatory and cell death responses that can be limited by treatment with the catalytic antioxidant EUK-207.     

Prevention of avian influenza epidemic: what policy should we choose?

Human-to-human transmission of the avian influenza has been extremely rarely reported, and is considered as limited, inefficient and unsustained. However, experts warn an occurrence of “mutant avian influenza”, which can easily spread among humans, because the avian influenza is already endemic, in particular in Asian poultry, and it is evolving in domestic and wild birds, pigs and humans. Outbreak of such mutant avian influenza in the human world may have devastating consequences, which are comparable with these for the 1918 “Spanish influenza”. In this paper we develop a mathematical model for the spread of the mutant avian influenza, and explore the effectivity of the prevention policies, namely the elimination policy which increases the effective additional death rate of the infected birds and the quarantine policy which reduces the number of infective contacts.     

Factors in the incidence of childlessness in Canada: An analysis of census data

The impact of the 1918 influenza pandemic on human fertility has been subject to significant scholarly debate. The current study characterizes the inter-temporal association between excess deaths during the pandemic and the subsequent birth deficit by identifying the length of time between these two phenomena using cross-correlations of monthly death and birth data from Taiwan from 1906 to 1943. The analysis demonstrates a strong and negative correlation between deaths (d) at time t and births (b) at time t + 9 (r_db(9) = –0.68, p < .0001). In other words, a significant drop in births was observed nine months after pandemic mortality peaked. The findings suggest that the 1918 influenza pandemic impacted subsequent births primarily through the mechanism of reduced conceptions and embryonic loss during the first month of pregnancy rather than through late-first-trimester embryonic loss.     

Dynamics of the glutamic acid 242 side chain in cytochrome c oxidase

In many cytochrome c oxidases glutamic acid 242 is required for proton transfer to the binuclear heme a₃/Cu_B site, and for proton pumping. When present, the side chain of Glu-242 is orientated “down” towards the proton-transferring D-pathway in all available crystal structures. A nonpolar cavity “above” Glu-242 is empty in these structures. Yet, proton transfer from Glu-242 to the binuclear site, and for proton-pumping, is well established, and the cavity has been proposed to at least transiently contain water molecules that would mediate proton transfer. Such proton transfer has been proposed to require isomerisation of the Glu-242 side chain into an “up” position pointing towards the cavity. Here, we have explored the molecular dynamics of the protonated Glu-242 side chain. We find that the “up” position is preferred energetically when the cavity contains four water molecules, but the “down” position is favoured with less water. We conclude that the cavity might be deficient in water in the crystal structures, possibly reflecting the “resting” state of the enzyme, and that the “up/down” equilibrium of Glu-242 may be coupled to the presence of active-site water molecules produced by O₂ reduction.