Influenza Pandemics

A Pandemic is a global outbreak or an epidemic of an infectious disease. Pandemics have swept the globe for over centuries and posed a significant threat to public health as well as social disruption and economic crisis. Previous and current pandemics include influenza virus pandemics [IVP], smallpox, malaria, tuberculosis, cholera and human-immuno-deficiency virus [HIV] etc. However, Smallpox has been the only disease that has been eradicated globally. The last reported case of smallpox was in 1977 and in 1980 WHO [World Health Organisation] declared the disease as eradicated and Dr Donald Henderson was awarded a medal for his work. It was a contagious and deadly acute disease caused by the Variola virus, which is a member of the Poxviridae family [genus: Orthopoxvirus]. There were 2 forms of the virus, variola major resulting in the deadly disease and minor which was a milder version of the disease [Alstrim] (WHO, 2009). The variola virus consisted of a large and complex structure. It has been established the smallpox virus originated over 3000 years ago in India or Egypt and has devastated many populations over centuries and claimed millions of lives with the first outbreak  known as the great plague of Athens in 430 B.C which was noted by the Greek historian Thucydides in “The Peloponnesian War”(Weir,2001). Pandemics such as malaria and cholera have been detected mainly amongst developing or under-developed countries (Fig. 4). Malaria is caused by a blood infection due to protozoan parasites of the genus Plasmodium with transmission from human-human [H-H] via Anopheles female mosquitoes. It has been noted 4 species of the malaria parasite infects humans, while most distributed forms are Plasmodium vivax [P.vivax] and Plasmodium malariae [P.malariae]. Historical characterization of the culprits in Europe has been either “benign tertian” [P.vivax] or “quarten” [P.malariae] periodic fevers. The benign forms of the disease were not associated with the severe and often fatal manifestations of the disease caused by Plasmodium falciparum resulted in “sub-tertian malignant” periodic fevers (Carter et al. 2002). The mortality involved with malaria has been in-direct effect of malarial infections combined with other infections and complications and the current status of the disease is represented in fig.4. Another pandemic that is flourishing and sweeping victims globally is HIV which consists of 2 distinct types; HIV-1 and HIV-2. HIV-1 is the most common form and continuous global focus and investment is required to manage as well as to eradicate the disease (Cohen et al.2008). More than 60 million have been victimised since the pandemic began while the mortality of the disease is around 25 million. The United Nations [UN] confirmed 33.2 million of the world population is positive for HIV-1 and a further 2.5 million new cases have been established globally according to reports in 2007 (WHO,2007). Due to the current epidemiological patterns of the distribution of HIV-1, most countries have established the disease as an epidemic amongst the homosexual community, sex workers, injecting drug workers and the regular partners of such subjects. IVP on the other hand, have been the most prominent and collectively have claimed the life’s of millions worldwide over centuries (Fig. 2 &3).

Introduction; Influenza

Influenza pandemics lack any pattern, and evidence indicates it is a result of viruses, and has been amongst human populations for centuries. The 20^th century alone has foreseen 3 major influenza viruses resulting in pandemics; H1N1 [1918] or Spanish flu, H2N2 or Asian flu [1957] and H3N2 or Hong Kong flu [1968] (Fig. 2 &3). These pandemics were a result of successful adaptation of hemagglutinin [HA] subtype to humans from animals causing antigenic shift. The presence of modern virology during the 1957 and 1968 influenza pandemics has enabled the scientific community to gain better understanding thus characterisation of the viruses. Upon analysis of amino acid sequences in all 8 genes of A/Brevig Mission/1/1918 virus (BM 1918), it was concluded that the virus was derived from avian precursors which were introduced to humans prior to the pandemic. However, these interpretations have been disputed due to the lack of virus or the presence of variant gene phylogenies contradicting the theory in existence. The H2N2/1957 and H3N2/1968 sequences contained strains resulting from genetic reassortment between avian and current human viruses. H2N2/1957 pandemic contained HA, neuroaminidase [NA] and PBI genes while the H3N2/1968 pandemic consisted of both avian HA and PBI genes (Figure 1). The H2N2/1957 pandemic emerged with a global outbreak of the virus and although, speculation surrounding the virus initiated in 1933 it was available for laboratory analysis during the pandemic except for subject above 70 years of age. The laboratory analysis in Melbourne, Washington D.C and London confided the culprit was a never seen virus alone and was lethal. This was followed by the publication of the article confirming the deaths of 250,000 patients in Hong Kong resulting in the recovery and analysis of the virus in the Walter Reed Army Institute for Research in Washington D.C. The virus was recognized by fixation tests as Influenza A which is of negative RNA strands part of the Orthomyxoviridae genus and was described having a different HA antigen compared to previous viruses with increased sialidase/neuroaminidase activity. Varying strains of the Asian virus also varied with respect to specific sensitivity to either non-specific inhibitors of HA or antibody neutralization. According to the animal studies conducted on the H2N2 virus (Figure 6), consisted of the same virulence characteristics as the previous influenza subtypes. The Asian virus pandemic provided the initial instance for vaccine response amongst large populations that lacked any exposure to the novel HA and NA antigens and was required in large quantities to provide a primary antibody response.

 Origin of the 1918 influenza virus

According to the analysis of evolutionary mechanism the H1N1/1918 virus (Fig.5) showed its existence in both humans and swine 2-15 years prior to the pandemic while phylogenetic analysis suggested the virus was generated via reassortment between mammalian and a previous non-pure avian human virus and was uniquely virulent. During this period bacteriology was flourishing and close analysis of post-mortem examinations by pathologists discovered bacteria in the lungs of the dead, although, it may have been caused by other infectious pathogens such as measles which was a common cause of death amongst the military personnel. Therefore the number of deaths caused during this period is inevitably questionable (Kilbourne E.D, 2006). The virulence of the influenza virus reduced during the 1930s-1950s, post 1918 pandemic consisting of regional epidemics. Virulence may be affected by the presence of novel surface proteins once a virus has gained characteristics required to transmit to populations that are composed of a rather naive immune system as in the case of the 3 pandemics that occurred during the 20^th century. Virulence factors of a particular virus is a series of complex processes involving factors such as immune status of the host, tropism of tissues, transmissibility, adaptation of the host and replication of the virus and its efficiency (Smith et al.2009). The features of any given influenza virus is therefore not fully understood even in the modern scientific error and are not fully characterized due to their genetic basis but is likely to exhibit polygenicity.

Historical background

The 1918 virus is thought to have initiated in the United States in the form of a “spring wave” while in Europe, North America and Asia the appearance of the virus was compared to a “fall wave” or “second wave” during September-November. During the pandemic, estimates reveal a third [500 million] of the world population may have been infected by the virus (Frost, 1920). The exceptionally severe disease consisted of mortality rates of about 2.5% amongst the infected while other influenza epidemics consisted of less than 0.1%. The 1890 pandemic was initiated during spring of 1889 and took a further several months to spread worldwide with peaks in Northern Europe and the United states in late 1889 or early 1890. The second or fall wave occurred during spring 1891 and a third followed in 1892. However, the 1918 produced 3 major outbreaks within the span of a year with its unique characteristics. It is unclear the reasons for the unusual rapid transmission of the virus although it has been suggested to have unique and effective mechanisms to invade the human immune system (Basler et al.2001).

Serology and Epidemiology

The genetic structure of the virus was analysed using frozen and fixed lung tissue of 5 victims of the 1918 pandemic with 2 male subjects from the U.S armed forces, 1 female subject from the Alaskan region and 2 from the Royal London Hospital. Functional and sequentional analysis of both NA and HA segments were conducted using autopsy tissue from the 5 subjects which composed of formalin and paraffin embedding and microscopic sections with haematoxylin and eosin staining. HA obtained from the victims comprised of 99% sequence identity with a difference in the 225^th amino acid residue. The sequence was closely related to the A/Swine/Iowa/30 virus alongside avian features. The immune system and antigenic drift targets 41 amino acids in a sequence in humans while 37 of these amino acids match avian sequences thus suggesting low level immunogenic pressure of the HA protein prior to 1918. Influenza viruses are able to invade human immune systems via the invasion of glycosylation sites which provides a mask to epitopes. Modern H1N1 virus consists of 5 glycosylation sites while avian sub-types consist of 9 (Gamblin et al.2004). However, the 1918 virus consisted of 4 avian sites within the HA. Sialic acid receptors on the surface of cells of hosts composed of HA proteins which influenza viruses require for binding. HA receptor sites consist of an invariant set of amino acids in the avian HA with variations amongst HAs of mammalian adaptations. Influenza viruses which are adapted to humans preferably bind to sialic acid receptors with α [2-6] links while viral strains which are adapted to birds bind to α [2-3] links. During shifting from an avian adapted receptor to a swine, H1s require the change of E190, an amino acid. This change was confirmed amongst the five 1918 pandemic victims with 2 of the cases identical to A/Swine/Iowa/30 HA while remaining 3 consisted of additional changes to G225D, another amino acid. The overall analysis of the crystal structure of 1918 HA suggested that the structure of the receptor binding site akin to H5 HA in that consisting of a narrow pouch than human H3HA confirming the 4 antigenic sites that were identified for another H1HA i.e. A/PR/8/34 virus. HA is the main antigenic determinant on 1918 H1N1 virus. Upon further analysis using X-rays the sites were shown to be exposed on 1918 HA prompting the easy recognition via the human immune system. The role of NA is to cleave sialic acid residues which are receptors for the viral HA protein. 1918 NA consisted of an active site with 15 amino acid residues with active sites located at a terminal knob on a thin stalk unlike some human virus strains which consist of 11-16 amino acids with areas of deletions. Both HA and NA of 1918 influenza virus lack evidence to suggest its genetic characteristics are related to virulence as two mutations that were known to other viruses such as the cleaving of HA to HA1 and HA2 by host proteases to be activated as a viral component and mutations at a particular codon site N146R or N146Y resulting in the elimination of a glycosylation site which enables the replication of the virus outside the respiratory tract were absent (Taubenberger, 2006). Therefore, the relationship between these proteins and virulence is unknown; however, their functional and structural features are avian like with mammalian adaptations.

Disease management

The World Health Organisation [WHO] has classified a pandemic in 6 phases; 1-6 (Fig.7) with each designed to inform the world of the seriousness and the management of the pandemic. Phase 1 is the period that lacks an animal influenza virus which may infect humans while phase 2 is the presence of an animal influenza virus that may be transmitted from wild or domestic animals to humans and pose a potential threat for a pandemic. Phase 3 is described as the period in which an animal influenza virus has resulted in sporadic cases amongst humans but lacks H-H transmission to result in community level outbreaks while phase 4 consists of H-H transmission between animals or human-animal influenza viruses resulting in community level outbreaks. Phase 5 describe the identification of the virus in community level outbreaks in 2 or more countries within a single WHO region while phase 6 is the same as phase 5 but with the addition of a single country within a second WHO region (WHO, 2007).

Treatment

Although vaccines were produced towards the end of the pandemic, the virus killed many of its victims. According to laboratory experiments the 1918 virus is similar to other 1918-like virus’s currently in circulation therefore the FDA-anti-influenza drugs such as rimantadine and oseltamivir would be sensitive to the virus. Other influenza anti-virals include NA inhibitors, RNA polymerase inhibitors, adamantanamine derivatives and IMP dehydrogenase inhibitors (Tumpey et al. 2002).

Conclusion

The 8 RNA segments of the 1918 virus has been analysed and their characterization has provided some knowledge of the origins of the virus. Furthermore, evidence strongly supports the hypothesis of the 1918 virus was a common ancestor of the subsequent human and swine H1N1 lineage. Although current sequential analysis has yet to provide distinctive clues to the genotypic basis of the exceptional virulence of the 1918 virus strain, experimental virulence models are being used with reverse genetic approaches to understand the 1918 virus from a new angle. The 1918 pandemic is unique due to its exceptionally high mortality. Clinical and pathological facts state the high mortality is due to elevated levels of severe and complicated respiratory tract infections and the concentration of the disease in a young age group. Also, the waves of the activity of the influenza virus kept re-appearing resulting in 3 major out breaks within the span of a year (Taubenberger, 2006). These unique characteristics define the genetic features of the Spanish influenza virus. However, current and future challenge will be to in gaining knowledge of the links between biological capabilities of the virus and its known history.