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INFLUENZA PANDEMIC (H1N1) (14): FINLAND, CROSS-REACTING ANTIBODY
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Date: Thu 4 Feb 2010
Source: Source: Eurosurveillance edition 2010; 15(5)
<http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19478>
High frequency of cross-reacting antibodies against 2009 pandemic
influenza A (H1N1) virus among the elderly in Finland
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[Authors: N Ikonen1, M Strengell1, L Kinnunen2, P Oesterlund1, J
Pirhonen1, M Broman1, I Davidkin1, T Ziegler1, I Julkunen1
1. Viral Infections Unit, National Institute for Health and Welfare
(THL), Helsinki, Finland
2 Diabetes Prevention Unit, National Institute for Health and Welfare
(THL), Helsinki, Finland]
[The Methods, extensive Tabulated data and Figures, and the References
have been omitted from this report. Interested readers should consult
the original article via the URL above. - Mod.CP]
Summary
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Since May 2009, the pandemic influenza A (H1N1) virus has been
spreading throughout the world. Epidemiological data indicate that the
elderly are underrepresented among the ill individuals. Approximately
1000 serum specimens collected in Finland in 2004 and 2005 from
individuals born between 1909 and 2005, were analysed by
haemagglutination-inhibition test for the presence of antibodies
against the 2009 pandemic influenza A(H1N1) and recently circulating
seasonal influenza A viruses. 96 per cent of individuals born between
1909 and 1919 had antibodies against the 2009 pandemic influenza
virus, while in age groups born between 1920 and 1944, the prevalence
varied from 77 per cent to 14 per cent. Most individuals born after
1944 lacked antibodies to the pandemic virus. In sequence comparisons
the haemagglutinin (HA) gene of the 2009 pandemic influenza A (H1N1)
virus was closely related to that of the Spanish influenza and 1976
swine influenza viruses. Based on the 3-dimensional structure of the
HA molecule, the antigenic epitopes of the pandemic virus HA are more
closely related to those of the Spanish influenza HA than to those of
recent seasonal influenza A (H1N1) viruses. Among the elderly,
cross-reactive antibodies against the 2009 pandemic influenza virus,
which likely originate from infections caused by the Spanish influenza
virus and its immediate descendants, may provide protective immunity
against the present pandemic virus.
Introduction
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In March and April 2009, a previously unknown variant of influenza A
(H1N1) virus was able to cause sporadic infection clusters and
epidemics in North America and Mexico. Rapid identification of the
virus indicated that it was a novel H1N1-reassortant influenza A virus
that originated from a triple reassortant North American swine
influenza A virus that had acquired 2 virus genes (NA and M) from an
Eurasian swine influenza A virus; the virus thus contains genetic
material from avian (PA and PB2), human (PB1) and 2 lineages of swine
influenza A viruses. Compared with seasonal H1N1 viruses the novel
virus is genetically and antigenically very different from human H1N1
viruses that have been circulating during the last 60 to 70 years.
Since the majority of the world's population is lacking immunity
against this new virus, it has been spreading throughout the world
with an unprecedented speed. On 11 Jun 2009, the World Health
Organization (WHO) declared the 1st pandemic of the 21st century to
have started, caused by the 2009 pandemic influenza A (H1N1) virus.
Epidemiological analyses initially from Mexico and the United States
(US), and later from Europe and the southern hemisphere revealed that
the disease is affecting children, young adults and the general
population under 65 years of age. Recent reports from Japan, the US,
and the United Kingdom (UK) have suggested that pre-existing
antibodies and thus cross-protection against the pandemic virus exist
in some individuals, especially those that are currently over 65 years
old. At present only limited data on this are available from Europe.
Rapid isolation and characterisation of the 2009 pandemic influenza
virus, the fast dissemination of the early virus isolates to
laboratories around the world, and the swift generation of reassortant
and recombinant vaccine viruses enabled vaccine manufacturers to start
mass production of pandemic virus vaccines rapidly. Presently, many
vaccine producers have been successful in preparing functional
vaccines and mass vaccinations are ongoing in a number of countries.
Following recommendations by the WHO, the European Centre for Disease
Prevention and Control (ECDC), and other relevant agencies, many
countries have made their own vaccination prioritisations, in which
health professionals, pregnant women, people with chronic underlying
diseases, and children and young adults are among the 1st groups to be
vaccinated. In order to have a better view of the possible
pre-existing cross-reactive immunity against the 2009 pandemic
influenza virus in the Finnish population we measured pre-existing
antibodies to this virus in more than 1000 serum samples collected in
2004 and 2005, long before the present pandemic, from individuals born
between the years 1909 and 2005.
Results
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Antibody levels
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Antibody levels against a representative 2009 pandemic influenza
virus, A/Finland/554/2009 showed that the oldest individuals (born
between 1909 and 1919) had a very high prevalence of antibodies to the
2009 pandemic influenza A (H1N1) virus. More than 96 per cent of these
individuals had detectable antibodies (titres of 10 or more), and in
more than 55 per cent of them, antibody titres of 40 or more were
detected, which is generally considered to be a protective level. In
younger age groups the prevalence of detectable antibodies against
2009 pandemic influenza virus decreased gradually with increasing year
of birth (tabulated in the original text). Only some (10-14 per cent)
of the individuals born between 1930 and 1949 had cross-reactive
antibodies against the pandemic virus. It is of note that some
individuals in the oldest age group had very high antibody levels with
HI titres ranging between 160 and 320. Antibodies against seasonal
H1N1 and H3N2 influenza viruses were found in 9-67 per cent and 39-90
per cent of all the individuals, respectively, depending on the age
group.
When the older age groups were divided into subgroups of 5 birth
years, a gradual decrease in the frequency and levels of antibodies
against the 2009 pandemic influenza virus was observed with increasing
year of birth, indicating that high antibody levels were only found in
individuals born in the mid 1920s or earlier. A relatively large
proportion of individuals in these age groups also had antibodies
against seasonal H1N1 and H3N2 influenza viruses.
Sequence comparisons
--------------------
Amino acid sequence comparisons between different HA sequences
revealed that the 3 1918 influenza HA1 proteins are almost identical
(99.7 per cent identity). More than 99 per cent sequence identity is
also shown between the 2009 pandemic viruses, which can be verified by
sequence comparison between any of the pandemic influenza HA genes
submitted to GenBank. It is of note that the seasonal influenza
viruses from the 1930s had already significantly drifted from the
Spanish influenza virus HA1 sequences and approximately 15 per cent of
the amino acids had been mutated giving an estimated evolutionary rate
of 1 per cent amino acid changes per year. The HA1 proteins of the
seasonal influenza A (H1N1) virus, A/Brisbane/59/2007, show
approximately 20 per cent divergence from that of the Spanish
influenza virus. Comparison of the 2009 pandemic influenza virus HA1
sequences revealed that the most closely related human H1N1 influenza
viruses were in fact the viruses of the Spanish influenza (16.8 to
17.1 divergence) with the exception of the swine virus that caused the
1976 outbreak in Fort Dix (10.8 to 11.0 divergence). The seasonal H1N1
influenza viruses isolated between 1933 and 2007 showed 23.0 to 27.8
per cent sequence differences to the pandemic H1N1 2009 virus (data
tabulated in the original text). Genetic data thus clearly indicate
that the closest relatives of the 2009 pandemic virus are the Spanish
influenza and Fort Dix virus strains.
Molecular and structural analysis
---------------------------------
[Assimilation of this section requires inspection of the figures and
graphical data and is omitted from this report. - Mod.CP]
Discussion and conclusion
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This study demonstrates that in Finland, individuals born between 1909
and 1924 and to a lesser extent those born between 1925 and 1944 have
pre-existing humoral immunity against the 2009 pandemic H1N1 influenza
A virus. Genetic and structural analyses also revealed that the 2009
pandemic virus is more closely related to the 1918 Spanish influenza
and to the 1976 Fort Dix outbreak swine viruses than to any other
seasonal H1N1-type influenza viruses that have been isolated since the
1930s. It is highly likely that immunity induced by the Spanish
influenza virus, as seen in the oldest individuals included in this
study, provides cross-protection against the currently circulating
2009 pandemic influenza virus.
The sera selected for this study represent very well the general
population in Finland since the diagnostic laboratory received samples
from all over the country and different age groups (0-96 years) were
included. Historical records also indicate that the Spanish influenza
was prevalent practically all around the world. In Finland the Spanish
influenza was highly prevalent and found in almost all corners of the
country including the most northern parts. In this respect our serum
material covers the Spanish influenza history in Finland very well, so
that our results are likely to be representative and informative for
the general situation in Europe. Recent studies from Japan, the US,
and the UK also describe the presence of cross-reactive antibodies to
the 2009 pandemic influenza virus among the oldest age groups (born in
1930 or earlier). If the cross-reactivity against the 2009 pandemic
influenza virus is indeed due to infections caused by the Spanish
influenza and/or its immediate descendant viruses in the late 1910s
and the 1920s, this would seem to suggest that specific anti-influenza
immunity can last for an extremely long time, even a lifetime. The
33-55 per cent of individuals who were born between the years 1909 and
1924 had relatively high antibody levels (40 or more HI titres)
against the 2009 pandemic influenza virus and are thus likely to be
protected against infection with this virus. Antibody levels of 40 or
higher as measured by the HI method are generally considered as
protective and such post-vaccination antibody levels are an indication
of an efficient vaccine-induced humoral immune response. There was
also a very good correlation between the level of cross-reactivity in
the older age groups and the evolution of the Spanish influenza virus
descendants. Even if there is a considerable gap in available virus
isolates and HA sequences between the years 1918 and 1933 we can
estimate the evolutionary speed of the virus to be at least 1 per cent
of HA1 amino acids changes per year. Apparently, the evolution was so
fast that the viruses circulating in the 1930s and 1940s were already
quite distinct from the initial Spanish influenza virus and thus
infections caused by those viruses were unable to induce significant
cross-reactivity against the 2009 pandemic influenza virus.
Based on HA sequence data, the 2009 pandemic influenza A (H1N1) virus
is more closely related to the Spanish influenza virus than to the
present day seasonal influenza A (H1N1) viruses. It is thus likely
that the Spanish influenza virus was transmitted from the human to the
swine population after the 1st wave of 1918 pandemic and the evolution
of the viral HA gene in pigs went on independently from that in
humans. However, since the HA proteins of the Spanish influenza and
the 2009 pandemic influenza virus show 17 per cent amino acid
divergence, this gives an estimated evolutionary rate of approximately
0.2 per cent amino acid changes per year, which is considerably slower
than usually seen among human seasonal influenza A (H1N1) viruses. It
is likely that the shorter life span of domestic pigs and their lack
of pre-existing immunity allowed the virus to spread in swine
populations without significant evolutionary pressure. In many ways
this may reflect the present situation with the 2009 pandemic virus,
which shows extremely low rates of evolution due to the lack of
protective immunity in the majority of the world's population. At
present, the amino acid changes from the HA and NA gene sequences of
the prototype pandemic strain and the and vaccine strain
A/California/7/2009 to those of currently circulating 2009 pandemic
influenza strains are less than 1 per cent and 0.5 per cent,
respectively. Thus, basically any 2009 pandemic influenza A (H1N1)
isolate can at present serve as a suitable strain for immunological
analyses and vaccine production.
The availability of the 3-dimensional structure of the 1918 influenza
virus HA molecule allowed us to seek for molecular and immunological
explanations of the humoral cross-reactivity between the Spanish
influenza and the 2009 pandemic influenza viruses. The analysis
clearly revealed that there are a number of amino acid differences in
the important antigenic epitopes on the surface of the HA molecule,
but these differences are far fewer between the 1918 Spanish influenza
and the 2009 pandemic influenza virus HA molecules as compared to the
differences seen between the 1918 Spanish influenza and seasonal
viruses from 1934 or 2007 or between the 2009 pandemic and the 2007
seasonal influenza HA molecules. Even though the comparison was done
by modelling, it can be assumed that the overall structure of the HA
molecule of H1 influenza viruses is highly conserved. All in all we
can say that the critical antigenic epitopes between the 1918 Spanish
influenza and the 2009 influenza viruses are at least partially
conserved, which probably explains the observation that people who
have been infected with the Spanish influenza virus or a closely
related virus have good cross-reactive immunity against the 2009
pandemic virus.
The present study, as well as a previous study showing the existence
of B cell clones specific for the Spanish influenza HA in the elderly,
indicate that immunological memory may last a whole lifetime. These
observations also suggest that the driving force of human influenza A
virus evolution is the host's immune response that stimulates
antigenic drift. Epidemiological analyses from North America, Europe,
and Australia of the underrepresentation of the elderly in population
groups contracting 2009 pandemic influenza suggest that persisting
immunity against the Spanish influenza virus and its early variants
may in fact give life-long immunity against the same or a very closely
related virus strain such as the 2009 pandemic influenza A (H1N1) virus.
--
Communicated by:
ProMED-mail
<promed@promedmail.org>
[The report above describes a coherent analysis of the occurrence of
cross-reacting antibodies against the pandemic influenza A (H1N1)
virus among the elderly in Finland. The essential conclusion is that
96 per cent of individuals born between 1909 and 1919 had antibodies
against the 2009 pandemic (H1N1) influenza virus, whereas in age
groups born between 1920 and 1944, the prevalence varied from 77 per
cent to 14 per cent, and most individuals born after 1944 lacked
antibodies to the pandemic (H1N1) virus. These data indicate that
specific anti-influenza immunity can last for an extremely long time,
even a lifetime. - Mod.CP]
[Regarding the authors' comment "These observations also suggest that
the driving force of human influenza A virus evolution is the host's
immune response that stimulates antigenic drift", postulating an
active process, I would suggest that there is no stimulation; rather,
the antibody supresses the majority variant, thus allowing minority
variants with small mutations to multiply disproportionately and take
over, a passive process. - Mod.JW]
[see also:
Influenza pandemic (H1N1) (13): vaccine recall 20100204.0379
Influenza pandemic (H1N1) (12): vaccine distribution, WHO update 20100202.0359
Influenza pandemic (H1N1) 2009 (123): vaccine safety 20091205.4152
Influenza pandemic (H1N1) 2009 (112): Canada (MB), vaccine reaction
20091121.4009
Influenza pandemic (H1N1) 2009 (67): vaccine delivery 20091011.3515
Influenza pandemic (H1N1) 2009 (63): USA military vaccine 20091002.3437
Influenza pandemic (H1N1) 2009 (55): vaccine formulation 20090925.3359
Influenza pandemic (H1N1) 2009 (54): vaccine availability 20090921.3325
Influenza pandemic (H1N1) 2009 (53): vaccine donation 20090919.3290
Influenza pandemic (H1N1) 2009 (49): FDA vaccine update 20090917.3254
Influenza pandemic (H1N1) 2009 (21): vaccine priorities 20090730.2669
Influenza pandemic (H1N1) 2009 (11): vaccine issues 20090722.2595
Influenza pandemic (H1N1) 2009 (10): vaccine 20090720.2577
Influenza pandemic (H1N1) 2009 (05): vaccine 20090716.2540
Influenza pandemic (H1N1) 2009 (03): vaccine 20090713.2505]
........................................cp/mj/jw
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