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The 2011 H1N1 Pandemic Fiasco
Recombinomics Commentary 14:50
January 1, 2011

Despite three people in East Yorkshire already dying from swine flu this year, Jim Deacon, assistant director of emergency planning for the NHS in the Humber region, insisted the threat is no greater than in the past.
Swine flu is the most predominant strain of flu this winter and is classed as part of seasonal flu.

Mr Deacon said deaths from seasonal flu are not as high as previous years and the fact the most common strain this year is swine flu is "not significant".

"But you would expect something like 2,000 deaths nationally from flu by this time of year and it is about 400 so far.

The above comments encapsulate the 2011 pandemic fiasco, an abject failure to control the spread of H1N1 in 2011, which is well represented by the health care crisis in the United Kingdom.

The fiasco really traces back to the SARS pandemic, when laboratory confirmation was used to define and quantify SARS coronavirus infections.  There was a clear need for an accurate number of cases because of the significant financial, political, and social impacts of infections, and shortly after the mysterious disease began to spread internationally, a laboratory test based on the novel coronovirus was in place and distributed worldwide.

However, the testing requirements provided a convenient mechanism for gaming the system by simply limiting testing.  Prior to the test China limited knowledge of the disease by simply not reporting cases.  They subsequently lowered the case fatality rate by increasing the number of mild cases tested.  However, Taiwan was the country that aggressively lowered its number of SARS cases by cremating bodies prior to sample collection and classifying these cases, which clinically matched SARS confirmed cases, as SARS-related cases, thereby cutting the number of SARS confirmed cases in half.

This manipulation of confirmed cases was quickly extended to influenza in general and H5N1 in particular.  The most effective way of limiting the spread of confirmed H5N1 cases was to simply not test.  Consequently, the H5N1 index cases for Cambodia, Indonesia, and China were not counted because samples were not collected, and the first confirmed cases in each country were contacts of the index cases.  The “not testing” approach was also widely applied to outbreaks in poultry and wild birds, initially in Asia, but subsequently in Europe, the Middle East, and Africa.
The testing requirement and associated gross undercounts were eventually applied to the 2009 H1N1 pandemic, leading to major misconceptions about the spread and gravity of the outbreak.  Infections in schools were underplayed because only lab confirmed cases were cited and the vast majority of infected students were not tested.  This allowed schools to remain open and the high levels of H1N1 undisclosed.  It also created a gross undercount of cases, which extended to severe and fatal cases.

The gross undercount was magnified by comparisons to historic levels of seasonal flu deaths.  In the United States the annual number was 36,000, but these were deaths of the frail and elderly who were estimated by death certificates and clinically defined cases, not lab confirmation.
These very different approaches in estimating seasonal and pandemic H1N1 deaths led to false comparisons, including media reports claiming the H1N1 was an infection that was much milder than seasonal flu, when lab confirmed deaths in young adults were compared to estimates of deaths of patients who were well over 65 years of age and battling long term health problems.

The public and in some cases agency perceptions of the false comparisons were compounded by the WHO proclamation on the end of pandemic phase of the 2009 H1N1 pandemic in August of 2010.  Although a new sub-clade was emerging in Australia and previously healthy young adults were dying in Australia and India, the pandemic phase was declared over because the seasonal H3N2 influenza A as well as influenza B began to re-emerge while pandemic H1N1 levels were low in the northern hemisphere.  However, and decline in the pandemic strain is the norm, which is due to the target population developing immunity.  However, the pandemic strain develops variants which can escape from the immune response, which produces a new wave, as is currently seen in the UK.

The UK H1N1 includes the sub-clade that was emerging in Australia when the WHO issued its August proclamation.  This sub-clade and other variants continue to evolve away from the 2009 vaccine target as well as immune responses generated against the H1N1 circulating last season, including the vaccine target A/California/7/2009, which is again the target for this season.

California/7 was not the ideal target.  Although it was circulating in southern California in early April of 2009, it had multiple HA differences with the sub-clade that was much more widespread.  Consequently, there were a few single amino acid changes that could produce low reactors, isolates that had a four fold or greater reduction in titer.

One such change was G158E, which was present in one of the first low reactors identified by the CDC, an isolate from Germany.  This association was not a surprise because Mill Hill had designated another isolate from Germany as a low reactor and both had D158E.  Moreover, escape mutants also had D158E, and MedImmune found that clones with D158E grew well in chicken eggs, but reacted poorly with anti-sera generated against California/7.

However, when D158E began to appear in US isolates, the CDC changed its assay, which no longer classified H1N1 isolates with G158E as low reactors.  Moreover, an isolate from the Ukraine, A/Lviv/N6/2009 had another change D225G, which Mill Hill designated as a low reactor.  The CDC published a sequence from that patient that had both G158E and D225G, but they still failed to designate that isolate as a low reactor.  The WHO regional center in Australia subsequently published antigenic characterization data which showed a sharp reduction in titer for A/Lviv/N6/2009, adding to the uncertainty about the CDC assay.

Indeed, the only low reactors from the United States identified by the CDC were those with changes at the adjacent position, 159, raising further doubt about the sensitivity of the CDC assay.

The change at position D225G also was critical in vaccine production.  Isolates with D at position 225 produce a low viral yield when grown in chicken eggs.  MedImmune used a clone with D225G and had a vaccine spray delivered weeks ahead of the vaccine shot because of differences in viral yield.  The delay in the shot was significant because the spike in fall H1N1 was early and had passed its peak by the time the vaccine shot shipped in quantity.  Thus, vaccine uptake in late 2009 / early 2010 was very low and the vaccine target for 2010/2011 was unchanged.
This initial low uptake was compounded by the WHO August proclamation on the pandemic phase.  The announcement of its end led to low vaccine uptake in the fall of 2010, as well as a relaxing of pandemic preparedness.

This reduction in preparedness has led to the current fiasco in the UK, which is now starting to appear in Europe, where H1N1 is the dominant strain in circulation and vaccine uptake is low.

The low vaccine uptake is compounded by the evolution of the H1N1, which was most obvious in Australia over the summer of 2010.  A new sub-clade emerged which was associated with vaccine breakthrough and severe cases.

The recently released sequences from the UK showed that this sub-clade has migrated to the UK, along with additional sub-clades that are drifting away from California/7 via recombination, which has reduce the effectiveness of the current vaccine, as well immunity generated against the H1N1 circulating last season.

These genetic changes have led to an explosion of severe H1N1 cases in the UK which is straining health care delivery.  A vaccine shortage has focused attention on patients with underlying conditions, even though approximately half of severe and fatal H1N1 cases have no underlying conditions.  These previously healthy young adults have a very low vaccine uptake and they are filling up ICU beds and crating an ECMO shortage.

The spike in severe cases has appeared early in the season and may increase dramatically in 2011, when more GP offices open and children return to school.  This health care delivery strain seen in the UK will almost certainly spread to Europe in the upcoming weeks, where vaccine uptake is also low and the new sub-clades of H1N1 will also target previously healthy young adults.

The above sequence of events will produce a 2011 pandemic fiasco where the emerging H1N1 will severely strain health care delivery throughout the northern hemisphere.

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