Q&A: H1N1 Pandemic Influenza - What's New?: Question & Answer Open Access
Q&A: H1N1 Pandemic Influenza - What's New?: Question & Answer Open Access
Q&A: H1N1 Pandemic Influenza - What's New?: Question & Answer Open Access
The World Health Organization has announced the instances within pig populations, the species from which
end of the (H1N1) influenza A (H1N1) pandemic - it emerged [2]. This increases the opportunity for the
what does this mean? virus to reassort with other avian and swine viruses to
In 2009, the new H1N1 pandemic virus exhibited several produce new influenza strains of unpredictable trans
features that distinguished it from seasonal influenza: it missibility and virulence [3]. (Figure 1 illustrates schema
caused major outbreaks in the northern hemisphere tically how new pandemic influenza viruses are thought
summer and autumn, it quickly dominated over other to arise.)
influenza viruses circulating in humans, and it caused
widespread disease because of the lack of significant Is there any sign of reassortment between different
population immunity, particularly in young people. In viruses?
2010, the pandemic virus is behaving more like a seasonal When we last wrote on this [4], there was no evidence of
influenza virus in that summer outbreaks have not been reassortment between the influenza (H1N1) 2009 virus
seen, it is co-circulating with seasonal A(H3N2) and B and other viruses, avian or seasonal. However, the recent
viruses, and the intensity of transmission is now lower re-introduction of influenza (H1N1) 2009 into swine that
than in 2009. For these reasons, the World Health we have just mentioned does provide the potential, if
Organization (WHO) downgraded its pandemic alert limited, of reassortment with other swine influenza
from phase 6 to the post-pandemic phase on 10 August viruses [3]. Also of concern, Octaviani and colleagues [5]
2010. Fortunately, in contrast to descriptions of the 1918 recently used a modified in vitro reassortment strategy to
Spanish influenza pandemic, there has been no apparent ask how easily the current pandemic virus could reassort
change in disease severity over the first 18 months of with a highly pathogenic H5N1 avian influenza, and
circulation of this virus. found, surprisingly, that 85% of the viruses they obtained
from this mixing experiment were reassortants. This
Does this mean that the pandemic H1N1 influenza means that there is excellent genetic compatibility
virus is no longer a threat? between these two viruses, a characteristic that had been
Not necessarily, not altogether. Several features of this difficult to show between HPAI H5N1 and seasonal
virus are a continued cause for concern; for example, influenza viruses current before the pandemic. Reassor
most hospitalizations and deaths are still in those under tant viruses containing the HPAI H5 and N1 components
60 years old. This is probably because people in this age with polymerase subunits from the H1N1 pandemic
group are less likely to be immune. Furthermore, of those virus were not only fit but could replicate better than the
people admitted to hospital in the USA with confirmed parent H5N1 virus. This highlights the need for
influenza (H1N1) 2009 pneumonia, almost two-thirds continued surveillance of influenza viruses in the various
end up in intensive care. Recent clinical studies have animal reservoirs, particularly in regions where HPAI
identified risk factors for severe disease that include, but H5N1 is endemic.
are not limited to, obesity, cardiovascular disease and
pregnancy. Importantly, however, about one-third of What about antigenic drift?
those who have died with (H1N1) 2009 lacked any known Despite intense surveillance by the WHO Global Influ
risk factors [1]. It is also of concern that the human enza Surveillance Network and other systems, significant
influenza (H1N1) 2009 virus can be found in limited antigenic drift has not yet been detected in circulating
H1N1 2009 viruses. However, we expect that it will
appear over the next year or so.
*Correspondence: [email protected] A key driver for antigenic drift in the influenza virus
1
Department of Microbiology and Immunology, The University of Melbourne,
Parkville, Victoria, 3010, Australia HA glycoprotein is immune pressure by the specific
Full list of author information is available at the end of the article antibody response. Recent serological analyses in a
© 2010 Turner et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Turner et al. BMC Biology 2010, 8:130 Page 2 of 6
http://www.biomedcentral.com/1741-7007/8/130
Figure 1. Mutation and reassortment giving rise to antigenic drift and antigenic shift in different hosts of influenza virus. The surface
hemagglutinin and neuraminidase molecules (blue) of influenza viruses, which play an essential part in viral recognition of and entry into host cells,
undergo frequent mutation (antigenic drift) in their human hosts, giving rise to new variants (red dots) that can elude antibodies made in many
individualshttp://jbiol.com/content/8/5/46/figure/F1
against the parent virus. Less frequently, entire segments of the eight-segment genome of an avian influenza virus and a human virus
become reassorted into the same virion, usually through infection of swine by both viruses, and this can result in a virus that is still adapted to infect
humans but expresses an avian hemagglutinin or neuraminidase (antigenic shift) to which there is no prior immunity in human populations. These
give rise periodically to pandemics. Figure reproduced with permission from Figure 10-17 of: DeFranco AL, et al. 2007 [24].
number of countries have found antibodies specific for influenza H1N1 2009 virus in most of the population.
the pandemic H1N1 virus in up to 40% of surveyed Comparison of the hemagglutinin structures of A/
individuals [6], suggesting exposure either by infection or California/04/2009 H1N1 and seasonal influenza viruses
by vaccination. The Centers for Disease Control and has shown significant variation within the antigenic sites
Prevention in the USA recently estimated there have recognized by specific antibodies [8]. In the same study, a
been 43 to 88 million cases of pandemic infection [7]. high degree of structural similarity between 2009 H1N1
Taken together, these data suggest that a large number of and 1918 H1N1-like viruses was also evident. Together
people are immune to the virus. So although it appears these analyses provide an explanation for the suscepti
that the threshold level of population immunity required bility of younger individuals and, conversely, the increased
to drive antigenic drift has not yet been reached, we resistance of older individuals who may have been
might expect antigenic variants to emerge over the next exposed to 1918-like H1N1 viruses in the first half of the
year or so as the pool of susceptible individuals declines. 20th century [9].
There are also indications that there may be less cross-
Are there any new clues to why susceptibility was protection from T-cell responses to earlier seasonal
so high, especially among younger people, in the viruses than had been supposed. Influenza-specific T-cell
first place? immunity is often directed against peptide components
Yes. What has emerged recently is a clear molecular derived from the more conserved internal viral gene
mechanism explaining the lack of immunity to the products, such as nucleoprotein, matrix protein 1 or
Turner et al. BMC Biology 2010, 8:130 Page 3 of 6
http://www.biomedcentral.com/1741-7007/8/130
polymerase subunits. T-cell immunity is therefore con immunity to one influenza virus is proposed to limit
sidered more able to provide heterologous immunity induction of immunity to subsequent infection with
because the targets are more likely to be shared between another. Importantly, in one individual admitted to the
different influenza strains and subtypes. There are studies intensive care unit with severe respiratory distress syn
that have demonstrated the presence of cross-reactive drome induced by pandemic infection, the same analysis
T cell responses between seasonal and pandemic influ of antibody responses demonstrated poor induction of
enza, supporting the notion that these responses may be specific antibody. These data together suggest that a
important in ameloriating infection in the absence of combination of underlying risk factors and an inability to
antibody immunity [10,11]. However, recent data suggest mount robust immune responses and to regulate pro-
this may not always be the case. Peptides from different inflammatory responses contributes to disease severity.
influenza strains and commonly targeted by the T-cell
response can vary extensively in amino acid sequence, Why is the virus so highly transmissible?
and even when they are able to bind the same major The efficiency of influenza A (H1N1) 2009 virus trans
histocompatibility complex (MHC) molecule (on which mission does not appear to be any greater than that of
they are presented for recognition by T cells), T cells seasonal influenza. A key factor in the rapid and
specific for one variant peptide may not recognize the sustained global spread of the virus during 2009 was the
other: this has been shown specifically for the seasonal as very large pool of susceptible individuals due to low
against the pandemic virus [12]. Thus, despite evidence population immunity.
that many individuals have pre-existing influenza-specific But there have been some recent advances in
T-cell immunity [13], these findings suggest that, just as identifying the molecular determinants of transmission -
with antibody immunity, previous exposure to one that is to say, the molecular factors that promote spread
subtype does not guarantee effective cross-protective of the virus between individuals. Using influenza reverse
immunity. This may also help to explain why the genetics, two groups introduced known virulence deter
pandemic virus was able to spread so quickly. minants into the influenza A (H1N1) 2009 pandemic
virus and used these viruses to study the impact of
Do we know any more about why some people are transmission in a ferret model of infection. Lysine at
particularly severely affected? position 627 of the PB2 protein has been reported to be a
It is clear that in animal models of infection, as well as in virulence determinant in the highly pathogenic HPAI
human clinical studies, the influenza A (H1N1) virus can H5N1 avian influenza virus [14] and is absent in the
replicate more extensively in the lower lung. Clinical data pandemic influenza (H1N1) 2009 viruses. Reassuringly,
have shown that key risk factors for more severe infection introduction of this mutation made very little difference
include obesity, diabetes and immunosuppression among to transmission efficiency and pathogenesis and in fact
other underlying conditions [1]. Clinical studies point to has been reported to attenuate transmission [15].
a lack of effective immunity and dysregulated pro-inflam Another factor is how well the virus binds to receptors
matory responses in those individuals worst affected by in the airways. There is clear evidence that specific amino
infection. For example, a paper presented at the recent acids in the hemagglutinin molecule, particularly within
Options for the Control of Influenza VII meeting in Hong the binding site whereby it recognizes its receptor on
Kong demonstrated that patients admitted to intensive cells, dictate specificity for either α2,3- or α2,6-linked
care had poor immune reactivity (T and B cell) combined sialic acids. Human influenza viruses have an aspartic
with pronounced production of pro-inflammatory acid (D) at positions 190 and 222 in the hemagglutinin
cytokines, particularly IL-6. In other unpublished data, at that impart α2,6-sialic acid binding. In contrast, the avian
the recent International Congress of Immunology in influenza virus preferentially recognizes α2,3-linked sialic
Japan, Rafi Ahmed presented a molecular characteriza acids, and this preference is determined by glutamic acid
tion of the specific B-cell response in pandemic-infected (E) and glycine (G) at positions 190 and 222, respectively.
individuals. By isolating specific B cells and cloning the Of particular interest was an experiment reported by
antibody receptors, he was able to take a census of the Tumpey and colleagues at the recent Options for the
types of antibodies induced after infection. Firstly, he Control of Influenza VII meeting in Hong Kong early in
showed that about a third of antibodies isolated from September. They used a mouse-adapted pandemic
those individuals who recovered quickly from infection (H1N1) strain with a D to G mutation at position 222 of
were derived from pre-existing memory B cells and had hemagglutinin [16]. This was predicted to reduce trans
undergone mutation. This resulted in a repertoire of anti mission and pathogenesis in their ferret model of
bodies that were more specific for pandemic than for infection. It failed to do either. What was of more interest
seasonal influenza. This goes against the ‘original was that introduction of a I219K mutation into the
antigenic sin’ theory, according to which pre-existing pandemic virus did result in increased transmission but
Turner et al. BMC Biology 2010, 8:130 Page 4 of 6
http://www.biomedcentral.com/1741-7007/8/130
no change in pathogenesis. This tells us that there is the pandemic (H1N1) strain) in Australia, probably
potential for these viruses to undergo further adaptation because of an effective public education program.
to human hosts and confirms the need for vigilance in According to recent Australian Government reports,
our surveillance. influenza activity is rising even though spring is now
beginning in Australia. It will be interesting to see
How far has the virus become resistant to whether the delay in onset of the influenza season and its
neuraminidase inhibitors? relatively low activity is due to the extensive vaccination
Two neuraminidase inhibitors have been widely used in program. We have to wait and see.
the prophylaxis or treatment of pandemic (H1N1)
influenza: oseltamivir (marketed as Tamiflu) and, to a Has there been any progress on making a
lesser extent, zanamivir (Relenza). Oseltamivir-resistant predictive vaccine or in the mode of flu vaccine
pandemic strains have been detected, often associated manufacture?
with prolonged treatment of severe cases, but to date The most important impediment to vaccine intervention
there is little evidence of sustained spread of these strains during the early stages of the pandemic was a delay in
among untreated individuals. As the most common availability. Although the full sequence of the new virus
oseltamivir resistance mutation (an H to Y change at was publicly available within days of its identification in
position 275) is close to the substrate-binding site of the April 2009 and a suitable vaccine strain was recommen
neuraminidase protein, it was expected from earlier ded by WHO just one month later, vaccine production
animal studies that such mutants would be less and deployment were significantly delayed by low virus
transmissible than their wild-type counterparts. There yields in eggs and a number of regulatory hurdles. As a
are conflicting data on this issue. For example, the H275Y consequence, there is a lot of interest in developing new
oseltamivir resistance mutation emerged in seasonal vaccine strategies that generate more broadly cross-
(H1N1) viruses in late 2007 and spread globally during reactive immunity. More recent advances have been in
2008 in the absence of widespread usage of the drug, generating antibody responses against conserved regions
suggesting that the mutation had not impaired viral of the hemagglutinin protein rather than the more
transmissibility. Subsequent work has identified variable regions found within the globular head of the
‘permissive’ mutations that restored the fitness of these protein. In a recent report, Gary Nabel and colleagues
viruses [17]. There are contradicting reports on the impact demonstrated that a DNA/recombinant adenovirus
of oseltamivir resistance on transmission of pandemic prime-boost strategy generated antibodies that cross-
influenza strains in ferret models, with one demonstrating reacted with antigenically distinct influenza strains [22].
lower transmission [18], and the other showing no impact They were able to demonstrate these cross-reactive
[19]. The reason for this difference is still unclear, so there antibodies target the more conserved stalk region. It is
is plainly a need to monitor the behavior of such drug- proposed that antibody binding in this region can impede
resistant viruses in humans carefully. the hemagglutinin conformational changes that are
required for virus infectivity. This has been taken a step
How effective has vaccination been? further by Peter Palese and colleagues [23], who used the
Initial clinical trials demonstrated that the monovalent hemagglutinin stalk region alone as the immunogen.
influenza (H1N1) 2009 vaccine is immunogenic and Again, actively targeting the stalk region in a vaccine
capable of inducing levels of antibody that are considered strategy induced cross-reactive antibodies, although
protective [20]. There is also evidence that vaccination protective efficacy is yet to be determined. Such strategies
reduces not only the risk of infection but also subsequent are promising but still have a way to go, particularly if
transmission to others [21]. Vaccination remains the single pharmaceutical companies are to commit to replacing
most effective method of protection from influenza. current vaccine formulations.
That said, it may still be too early to tell just how
effective vaccination against the pandemic virus has Looking to the future - how quickly would we know
been. There are two reasons for this. The first is that the if we had a new virus?
initial roll-out of the vaccine occurred too late to affect Although it took only a few days from initial identification
the first pandemic wave. For example, Australia received of the influenza (H1N1) 2009 virus in Mexico and
the monovalent vaccine in late September 2009. California in April to the announcement by WHO that its
Although this was only 5 months after selection of the emergence was a public health event of international
vaccine strain, winter was over and the initial pandemic concern (indicating its pandemic potential), the virus had
wave had subsided. Importantly, there has been strong in fact been circulating in humans for at least 2 months.
collective uptake of the monovalent pandemic vaccine Could we have acted earlier to prevent or reduce the
and the later trivalent seasonal vaccine (which included impact of the pandemic? More specifically, if we had
Turner et al. BMC Biology 2010, 8:130 Page 5 of 6
http://www.biomedcentral.com/1741-7007/8/130