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 20th 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 20th 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 225th
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.