Lessons learned from the 1918–1919 influenza pandemic

The 1918 influenza pandemic was one of the most virulent strains of influenza in history. Phylogenic evidence of the novel H1N1 strain of influenza discovered in Mexico last spring (2009) links it to the 1918 influenza strain. With information gained from analyzing viral genetics, public health records and advances in medical science we can confront the 2009 H1N1 influenza on a global scale. The paper analyses the causes and characteristics of a pandemic, and major issues in controlling the spread of the disease. Wide public vaccination and open communication between government and health sciences professionals will be an essential and vital component in managing the 2009 H1N1 pandemic and any future pandemics.     

Influenza A: From highly pathogenic H5N1 to pandemic 2009 H1N1. Epidemiology and clinical features

The last decade has seen the emergence of two new influenza A subtypes and they have become a cause of concern for the global community. These are the highly pathogenic H5N1 influenza A virus (H5N1) and the Pandemic 2009 influenza H1N1 virus. Since 2003 the H5N1 virus has caused widespread disease and death in poultry, mainly in south East Asia and Africa. In humans the number of cases infected with this virus is few but the mortality has been about 60%. Most patients have presented with severe pneumonia and acute respiratory distress syndrome. The second influenza virus, the pandemic H1N1 2009, emerged in Mexico in March this year. This virus acquired the ability for sustained human to human spread and within a few months spread throughout the world and infected over 4 lakh individuals. The symptoms of infection with this virus are similar to seasonal influenza but it currently affecting younger individuals more often. Fortunately the mortality has been low. Both these new influenza viruses are currently circulating and have different clinical and epidemiological characteristics.     

Transmission characteristics of the 2009 H1N1 influenza pandemic: comparison of 8 Southern hemisphere countries

While in Northern hemisphere countries, the pandemic H1N1 virus (H1N1pdm) was introduced outside of the typical influenza season, Southern hemisphere countries experienced a single wave of transmission during their 2009 winter season. This provides a unique opportunity to compare the spread of a single virus in different countries and study the factors influencing its transmission. Here, we estimate and compare transmission characteristics of H1N1pdm for eight Southern hemisphere countries/states: Argentina, Australia, Bolivia, Brazil, Chile, New Zealand, South Africa and Victoria (Australia). Weekly incidence of cases and age-distribution of cumulative cases were extracted from public reports of countries'' surveillance systems. Estimates of the reproduction numbers, R ₀, empirically derived from the country-epidemics'' early exponential phase, were positively associated with the proportion of children in the populations (p = 0.004). To explore the role of demography in explaining differences in transmission intensity, we then fitted a dynamic age-structured model of influenza transmission to available incidence data for each country independently, and for all the countries simultaneously. Posterior median estimates of R ₀ ranged 1.2–1.8 for the country-specific fits, and 1.29–1.47 for the global fits. Corresponding estimates for overall attack-rate were in the range 20–50%. All model fits indicated a significant decrease in susceptibility to infection with age. These results confirm the transmissibility of the 2009 H1N1 pandemic virus was relatively low compared with past pandemics. The pattern of age-dependent susceptibility found confirms that older populations had substantial – though partial - pre-existing immunity, presumably due to exposure to heterologous influenza strains. Our analysis indicates that between-country-differences in transmission were at least partly due to differences in population demography.     

Revealing the True Incidence of Pandemic A(H1N1)pdm09 Influenza in Finland during the First Two Seasons — An Analysis Based on a Dynamic Transmission Model

The threat of the new pandemic influenza A(H1N1)pdm09 imposed a heavy burden on the public health system in Finland in 2009-2010. An extensive vaccination campaign was set up in the middle of the first pandemic season. However, the true number of infected individuals remains uncertain as the surveillance missed a large portion of mild infections. We constructed a transmission model to simulate the spread of influenza in the Finnish population. We used the model to analyse the two first years (2009-2011) of A(H1N1)pdm09 in Finland. Using data from the national surveillance of influenza and data on close person-to-person (social) contacts in the population, we estimated that 6% (90% credible interval 5.1 – 6.7%) of the population was infected with A(H1N1)pdm09 in the first pandemic season (2009/2010) and an additional 3% (2.5 – 3.5%) in the second season (2010/2011). Vaccination had a substantial impact in mitigating the second season. The dynamic approach allowed us to discover how the proportion of detected cases changed over the course of the epidemic. The role of time-varying reproduction number, capturing the effects of weather and changes in behaviour, was important in shaping the epidemic.     

Lessons from pandemic H1N1 2009 to improve prevention, detection, and response to influenza pandemics from a One Health perspective

In April 2009, a novel influenza A subtype H1N1 triple reassortant virus (novel H1N1 2009), composed of genes from swine, avian, and human influenza A viruses, emerged in humans in the United States and Mexico and spread person-to-person around the world to become the first influenza pandemic of the 21st century. The virus is believed to have emerged from a reassortment event involving a swine virus some time in the past 10 to 20 years, but pigs, pork, and pork products have not been involved with infection or spread of the virus to or among people. Because countries quickly implemented recently developed pandemic influenza plans, the disease was detected and reported and public health authorities instituted control measures in a timely fashion. But the news media's unfortunate and inappropriate naming of the disease as the "swine flu" led to a drop in the demand for pork and several countries banned pork imports from affected countries, resulting in serious negative economic impacts on the pork industry. With the continual circulation and interspecies transmission of human, swine, and avian influenza viruses in countries around the world, there are calls for strengthening influenza surveillance in pigs, birds, and other animals to aid in monitoring and assessing the risk of future pandemic virus emergence involving different species. We identify and discuss several lessons to be learned from pandemic H1N1 2009 from a One Health perspective, as stronger collaboration among human, animal, and environmental health sectors is necessary to more effectively prevent or detect and respond to influenza pandemics and thus improve human, animal, and environmental health and well-being.     

Transmission of a 2009 pandemic influenza virus shows a sensitivity to temperature and humidity similar to that of an H3N2 seasonal strain

In temperate regions of the world, influenza epidemics follow a highly regular seasonal pattern, in which activity peaks in midwinter. Consistently with this epidemiology, we have shown previously that the aerosol transmission of a seasonal H3N2 influenza virus is most efficient under cold, dry conditions. With the 2009 H1N1 pandemic, an exception to the standard seasonality of influenza developed: during 2009 in the Northern Hemisphere, an unusually high level of influenza virus activity over the spring and summer months was followed by a widespread epidemic which peaked in late October, approximately 2.5 months earlier than usual. Herein we show that aerosol transmission of a 2009 pandemic strain shows a dependence on relative humidity and temperature very similar to that of a seasonal H3N2 influenza virus. Our data indicate that the observed differences in the timings of outbreaks with regard to the seasons are most likely not due to intrinsic differences in transmission between the pandemic H1N1 and seasonal H3N2 influenza viruses.     

Aerosol influenza transmission risk contours: A study of humid tropics versus winter temperate zone

Background

In recent years, much attention has been given to the spread of influenza around the world. With the continuing human outbreak of H5N1 beginning in 2003 and the H1N1 pandemic in 2009, focus on influenza and other respiratory viruses has been increased. It has been accepted for decades that international travel via jet aircraft is a major vector for global spread of influenza, and epidemiological differences between tropical and temperate regions observed. Thus we wanted to study how indoor environmental conditions (enclosed locations) in the tropics and winter temperate zones contribute to the aerosol spread of influenza by travelers. To this end, a survey consisting of 632 readings of temperature (T) versus relative humidity (RH) in 389 different enclosed locations air travelers are likely to visit in 8 tropical nations were compared to 102 such readings in 2 Australian cities, including ground transport, hotels, shops, offices and other publicly accessible locations, along with 586 time course readings from aircraft.

Results

An influenza transmission risk contour map was developed for T versus RH. Empirical equations were created for estimating: 1. risk relative to temperature and RH, and 2. time parameterized influenza transmission risk. Using the transmission risk contours and equations, transmission risk for each country's locations was compared with influenza reports from the countries. Higher risk enclosed locations in the tropics included new automobile transport, luxury buses, luxury hotels, and bank branches. Most temperate locations were high risk.

Conclusion

Environmental control is recommended for public health mitigation focused on higher risk enclosed locations. Public health can make use of the methods developed to track potential vulnerability to aerosol influenza. The methods presented can also be used in influenza modeling. Accounting for differential aerosol transmission using T and RH can potentially explain anomalies of influenza epidemiology in addition to seasonality in temperate climates.     

FluTE,a Publicly Available Stochastic Influenza Epidemic Simulation Model

Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development.     

Effect of vaccines and antivirals during the major 2009 A(H1N1) pandemic wave in Norway--and the influence of vaccination timing

To evaluate the impact of mass vaccination with adjuvanted vaccines (eventually 40% population coverage) and antivirals during the 2009 influenza pandemic in Norway, we fitted an age-structured SEIR model using data on vaccinations and sales of antivirals in 2009/10 in Norway to Norwegian ILI surveillance data from 5 October 2009 to 4 January 2010. We estimate a clinical attack rate of approximately 30% (28.7-29.8%), with highest disease rates among children 0-14 years (43-44%). Vaccination started in week 43 and came too late to have a strong influence on the pandemic in Norway. Our results indicate that the countermeasures prevented approximately 11-12% of potential cases relative to an unmitigated pandemic. Vaccination was found responsible for roughly 3 in 4 of the avoided infections. An estimated 50% reduction in the clinical attack rate would have resulted from vaccination alone, had the campaign started 6 weeks earlier. Had vaccination been prioritized for children first, the intervention should have commenced approximately 5 weeks earlier in order to achieve the same 50% reduction. In comparison, we estimate that a non-adjuvanted vaccination program should have started 8 weeks earlier to lower the clinical attack rate by 50%. In conclusion, vaccination timing was a critical factor in relation to the spread of the 2009 A(H1N1) influenza. Our results also corroborate the central role of children for the transmission of A(H1N1) pandemic influenza.     

Adaptive Vaccination Strategies to Mitigate Pandemic Influenza: Mexico as a Case Study

Background

We explore vaccination strategies against pandemic influenza in Mexico using an age-structured transmission model calibrated against local epidemiological data from the Spring 2009 A(H1N1) pandemic.

Methods and Findings

In the context of limited vaccine supplies, we evaluate age-targeted allocation strategies that either prioritize youngest children and persons over 65 years of age, as for seasonal influenza, or adaptively prioritize age groups based on the age patterns of hospitalization and death monitored in real-time during the early stages of the pandemic. Overall the adaptive vaccination strategy outperformed the seasonal influenza vaccination allocation strategy for a wide range of disease and vaccine coverage parameters.

Conclusions

This modeling approach could inform policies for Mexico and other countries with similar demographic features and vaccine resources issues, with regard to the mitigation of the S-OIV pandemic. We also discuss logistical issues associated with the implementation of adaptive vaccination strategies in the context of past and future influenza pandemics.     

Epidemiological update on swine influenza (H1N1) in pigs

The 2009 H1N1 pandemic has slowed down its spread after initial speed of transmission. The conventional swine influenza H1N1 virus (SIV) in pig populations worldwide needs to be differentiated from pandemic H1N1 influenza virus, however it is also essential to know about the exact role of pigs in the spread and mutations taking place in pig-to-pig transmission. The present paper reviews epidemiological features of classical SIV and its differentiation with pandemic influenza.     

Molecular character of influenza A/H1N1 2009: Implications for spread and control

The world is experiencing a pandemic of influenza that emerged in March 2009, due to a novel strain designated influenza A/H1N1 2009. This strain is closest in molecular sequence to swine influenza viruses, but differs from all previously known influenza by a minimum of 6.1%, and from prior “seasonal” H1N1 by 27.2%, giving it great potential for widespread human infection. While spread into India was delayed for two months by an aggressive interdiction program, since 1 August 2009 most cases in India have been indigenous. H1N1 2009 has differentially struck younger patients who are naïve susceptibles to its antigenic subtype, while sparing those >60 who have crossreactive antibody from prior experience with influenza decades ago and the 1977 “swine flu” vaccine distributed in the United States. It also appears to more severely affect pregnant women. It emanated from a single source in central Mexico, but its precise geographical and circumstantial origins, from either Eurasia or the Americas, remain uncertain. While currently a mild pandemic by the standard of past pandemics, the seriousness of H1N1 2009 especially among children should not be underestimated. There is potential for the virus, which continues to adapt to humans, to change over time into a more severe etiologic agent by any of several foreseeable mutations. Mass acceptance of the novel H1N1 2009 vaccine worldwide will be essential to its control. Having spread globally in a few months, affecting millions of people, it is likely to remain circulating in the human population for a decade or more.     

Comparative analysis of hemagglutinin of 2009 H1N1 influenza A pandemic indicates its evolution to 1918 H1N1 pandemic

To gain insight into the possible origin of the hemagglutinin of 2009 outbreak, we performed its comparative analysis with hemagglutinin of influenza viral strains from 2005 to 2008 and the past pandemics of 1977, 1968, 1957 and 1918. This insilico analysis showed a maximum sequence similarity between 2009 and 1918 pandemics. Primary structure analysis, antigenic and glycosylation site analyses revealed that this protein has evolved from 1918 pandemic. Phylogenetic analysis of HA amino acid sequence of 2009 influenza A(H1N1) viruses indicated that this virus possesses a distinctive evolutionary trait with 1918 influenza A virus. Although the disordered sequences are different among all the isolates, the disordered positions and sequences between 2009 and 1918 isolates show a greater similarity. Thus these analyses contribute to the evidence of the evolution of 2009 pandemic from 1918 influenza pandemic. This is the first computational evolutionary analysis of HA protein of 2009 H1N1 pandemic.     

The beginning and ending of a respiratory viral pandemic-lessons from the Spanish flu

The COVID-19 pandemic goes into its third year and the world population is longing for an end to the pandemic. Computer simulations of the future development of the pandemic have wide error margins and predictions on the evolution of new viral variants of SARS-CoV-2 are uncertain. It is thus tempting to look into the development of historical viral respiratory pandemics for insight into the dynamic of pandemics. The Spanish flu pandemic of 1918 caused by the influenza virus H1N1 can here serve as a potential model case. Epidemiological observations on the shift of influenza mortality from very young and old subjects to high mortality in young adults delimitate the pandemic phase of the Spanish flu from 1918 to 1920. The identification and sequencing of the Spanish flu agent allowed following the H1N1 influenza virus after the acute pandemic phase. During the 1920s H1N1 influenza virus epidemics with substantial mortality were still observed. As late as 1951, H1N1 strains of high virulence evolved but remained geographically limited. Until 1957, the H1N1 virus evolved by accumulation of mutations (‘antigenic drift’) and some intratypic reassortment. H1N1 viruses were then replaced by the pandemic H2N2 influenza virus from 1957, which was in 1968 replaced by the pandemic H3N2 influenza virus; both viruses were descendants from the Spanish flu agent but showed the exchange of entire gene segments (‘antigenic shift’). In 1977, H1N1 reappeared from an unknown source but caused only mild disease. However, H1N1 achieved again circulation in the human population and is now together with the H3N2 influenza virus an agent of seasonal influenza winter epidemics.     

Optimizing tactics for use of the U.S. antiviral strategic national stockpile for pandemic influenza

In 2009, public health agencies across the globe worked to mitigate the impact of the swine-origin influenza A (pH1N1) virus. These efforts included intensified surveillance, social distancing, hygiene measures, and the targeted use of antiviral medications to prevent infection (prophylaxis). In addition, aggressive antiviral treatment was recommended for certain patient subgroups to reduce the severity and duration of symptoms. To assist States and other localities meet these needs, the U.S. Government distributed a quarter of the antiviral medications in the Strategic National Stockpile within weeks of the pandemic's start. However, there are no quantitative models guiding the geo-temporal distribution of the remainder of the Stockpile in relation to pandemic spread or severity. We present a tactical optimization model for distributing this stockpile for treatment of infected cases during the early stages of a pandemic like 2009 pH1N1, prior to the wide availability of a strain-specific vaccine. Our optimization method efficiently searches large sets of intervention strategies applied to a stochastic network model of pandemic influenza transmission within and among U.S. cities. The resulting optimized strategies depend on the transmissability of the virus and postulated rates of antiviral uptake and wastage (through misallocation or loss). Our results suggest that an aggressive community-based antiviral treatment strategy involving early, widespread, pro-rata distribution of antivirals to States can contribute to slowing the transmission of mildly transmissible strains, like pH1N1. For more highly transmissible strains, outcomes of antiviral use are more heavily impacted by choice of distribution intervals, quantities per shipment, and timing of shipments in relation to pandemic spread. This study supports previous modeling results suggesting that appropriate antiviral treatment may be an effective mitigation strategy during the early stages of future influenza pandemics, increasing the need for systematic efforts to optimize distribution strategies and provide tactical guidance for public health policy-makers.     

Unseasonal Transmission of H3N2 Influenza A Virus During the Swine-Origin H1N1 Pandemic

The initial wave of swine-origin influenza A virus (pandemic H1N1/09) in the United States during the spring and summer of 2009 also resulted in an increased vigilance and sampling of seasonal influenza viruses (H1N1 and H3N2), even though they are normally characterized by very low incidence outside of the winter months. To explore the nature of virus evolution during this influenza “off-season,” we conducted a phylogenetic analysis of H1N1 and H3N2 sequences sampled during April to June 2009 in New York State. Our analysis revealed that multiple lineages of both viruses were introduced and cocirculated during this time, as is typical of influenza virus during the winter. Strikingly, however, we also found strong evidence for the presence of a large transmission chain of H3N2 viruses centered on the south-east of New York State and which continued until at least 1 June 2009. These results suggest that the unseasonal transmission of influenza A viruses may be more widespread than is usually supposed.The recent emergence of swine-origin H1N1 influenza A virus (pandemic H1N1/09) in humans has heightened awareness of how the burden of morbidity and mortality due to influenza is associated with the appearance of new genetic variants (5) and of the genetic and epidemiological determinants of viral transmission (8). The emergence of pandemic H1N1/09 is also unprecedented in recorded history as it means that three antigenically distinct lineages of influenza A virus—pandemic H1N1/09 and the seasonal H1N1 and H3N2 viruses— currently cocirculate within human populations.Although the presence of multiple subtypes of influenza A virus may place an additional burden on public health resources, it also provides a unique opportunity to compare the patterns and dynamics of evolution in these viruses on a similar time scale. Indeed, one of the most interesting secondary effects of the current H1N1/09 pandemic has been an increased vigilance for cases of influenza-like illness and hence an intensified sampling of seasonal H1N1 and H3N2 viruses during the typical influenza “off-season” (i.e., spring-summer) in the northern hemisphere. Because the influenza season in the northern hemisphere generally runs from November through March, with a usual peak in January or February, influenza viruses sampled outside of this period are of special interest.The current model for the global spatiotemporal dynamics of influenza A virus is that the northern and southern hemispheres represent ecological “sinks” for this virus, with little ongoing viral transmission during the summer months (9). In contrast, more continual viral transmission occurs within the tropical “source” population (13) that is most likely centered on an intense transmission network in east and southeast Asia (10). However, the precise epidemiological and evolutionary reasons for this major geographic division, and for the seasonality of influenza A virus in general, remain uncertain (1, 4). Evidence for this “sink-source” ecological model is that viruses sampled from successive seasons in localities such as New York State do not usually form linked clusters on phylogenetic trees, indicating that they are not connected by direct transmission through the summer months (7). Similar conclusions can be drawn for the United States as a whole and point to multiple introductions of phylogenetically distinct lineages during the winter (6), followed by complex patterns of spatial diffusion (14). However, despite the growing epidemiological and phylogenetic data supporting this model, it is also evident that there is relatively little sequence data from seasonal influenza viruses that are sampled from April to October in the northern hemisphere. Hence, it is uncertain whether extended chains of transmission can occur during this time period, even though this may have an important bearing on our understanding of influenza seasonality.To address these issues, we examined the evolutionary behavior of seasonal H1N1 and H3N2 viruses as they cocirculated during a single time period—(late) April to June 2009—within a single locality (New York State). Not only are levels of influenza virus transmission in the northern hemisphere usually very low during this time period, but in this particular season the human host population was also experiencing the emerging epidemic of pandemic H1N1/09.     

A single amino acid in the HA of pH1N1 2009 influenza virus affects cell tropism in human airway epithelium, but not transmission in ferrets

The first pandemic of the 21(st) century, pandemic H1N1 2009 (pH1N1 2009), emerged from a swine-origin source. Although human infections with swine-origin influenza have been reported previously, none went on to cause a pandemic or indeed any sustained human transmission. In previous pandemics, specific residues in the receptor binding site of the haemagglutinin (HA) protein of influenza have been associated with the ability of the virus to transmit between humans. In the present study we investigated the effect of residue 227 in HA on cell tropism and transmission of pH1N1 2009. In pH1N1 2009 and recent seasonal H1N1 viruses this residue is glutamic acid, whereas in swine influenza it is alanine. Using human airway epithelium, we show a differential cell tropism of pH1N1 2009 compared to pH1N1 2009 E227A and swine influenza suggesting this residue may alter the sialic acid conformer binding preference of the HA. Furthermore, both pH1N1 2009 E227A and swine influenza multi-cycle viral growth was found to be attenuated in comparison to pH1N1 2009 in human airway epithelium. However this altered tropism and viral growth in human airway epithelium did not abrogate respiratory droplet transmission of pH1N1 2009 E227A in ferrets. Thus, acquisition of E at residue 227 was not solely responsible for the ability of pH1N1 2009 to transmit between humans.     

Effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the influenza pandemic H1N1 2009 vaccine: a randomized controlled trial

Vaccination with the non-adjuvanted split-virion A/California/7/2009 influenza vaccine (pandemic H1N1 2009 vaccine) began in October 2009 in Japan. The present study was designed to assess the effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the pandemic H1N1 2009 vaccine in healthy adult volunteers. One hundred and seventeen participants aged 22 to 62 were randomly assigned to two study groups. In Group 1 (the priming group), participants were first vaccinated with the seasonal trivalent influenza vaccine followed by two separate one-dose vaccinations of the pandemic H1N1 2009 vaccine, whereas in Group 2 (the non-priming group), the participants were first vaccinated with one dose of the pandemic H1N1 2009 vaccine, followed by simultaneous vaccination of the seasonal trivalent vaccine and the second dose of the pandemic H1N1 2009 vaccine. The participants in Group 2 had a seroprotection rate (SPR) of 79.7% and a seroconversion rate (SCR) of 79.7% in the hemagglutination-inhibition test after the first dose of the pandemic H1N1 2009 vaccine, indicating that the pandemic H1N1 2009 vaccine is sufficiently immunogenic. On the other hand, the participants of Group 1 had a significantly weaker antibody response, with a SPR of 60.8% and a SCR of 58.5%. These results indicate that prior vaccination with the seasonal trivalent influenza vaccine inhibits the antibody response to the pandemic H1N1 2009 vaccine. Therefore, the pandemic H1N1 2009 vaccine should be administered prior to vaccination with the seasonal trivalent influenza vaccine.