Mike Osterholm, of CIDRAP at the University of Minnesota, makes the point that such descriptions hinder us from remembering the true impacts from the pandemic and learning the right lessons.

Though H1N1 was of low pathogenicity overall, when it struck, it hit hard disproportionately against the young, who were immunologically naive, and against pregnant women, who have lower overall immunity. The average age of those who died was 34.7 years. Hence measures that factor in age, such as Years of Life Lost, show a much higher societal impact of H1N1.

Severe H1N1 cases involved deep lung infections and with tissue necrosis, soon followed by respiratory failure. This had of the effect of straining hospital intensive care units (ICU’s) to their operational limits, across several countries. In Australia, ICU’s were reportedly “at the point of collapse” in 2009. Hospitals in the U.S. adjusted visitation policies to limit the potential spread of infection.

Contrary to expectations, the second H1N1 wave reemerged in late summer continuing into the the school year, leading to record numbers of school closures, something that is not typical of normal flu epidemics. Though exactly hard to determine, school closures probably had some spillover effect on lost economic output, and productivity owing to worker absenteeism

In late October and mid November as the second H1N1 pandemic wave intensified, and as H1N1 deaths surged, there were insufficient vaccine supplies on hand to meet peak demand. A switch to cell-based methods of vaccine production, along with improved distribution methods, could have saved lives.

ABC: Swine flu put hospitals ‘on edge’ last year
Medscape Medical News: Lessons Learned From the H1N1 Pandemic Are Meager

A universal flu vaccine, that can provide extended protection across a variety of recombitant influenza viruses represents the pinnacle for microbiological research in this area. While this goal remains years away, there are some promising lines of approach.

Current influenza vaccines essentially are aimed at narrow range of viruses that are currently in circulation. “Frequent minor changes in flu viruses involve two surface proteins, hemagglutinin and neuraminidase, represented by the H and N in virus names.”

The hemagglutanin (HA) surface protein is a “mushroom-shaped structure helps the virus attach to the cells it infects” The problem arises when the HA attack surface changes due to antigenic drift, requiring annual updates to the seasonal flu vaccine. Hence, some modern lines of research toward a universal vaccine try to take aim at those sections of HA portion of the virus that are relatively static over time and are consistent over several strains.

Researchers at Mount Sinai School of Medicine in New York developed
a proof-of-concept designed to help the immune system develop antibodies that target a headless hemagglutanin (HA) molecule. Thus far trials have proven successful in mice.

Other lines of research over recent years have taken aim at “M2″, a relatively stable protein found in Influenza A viruses.

Other molecular research has not centered on influenza virus itself but rather on finding human host factors and classes of natural flu fighting proteins that inhibit virus replication.

CIDRAP: Acambis launches human trial of ‘universal’ flu vaccine
CIDRAP: Firm says ‘universal’ flu vaccine passed early test
mBio: Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain
Reuters: Researchers take step to ‘universal’ flu vaccine

According to reporting from the World Health Organization (WHO) H1N1 Influenza Vaccine Task Force, global influenza vaccine production continues to fall well short of WHO’s desired production targets owing to a variety of factors.

In 2006, WHO set a goal of having vaccine supplies sufficient for two billion persons within six months of the provision of a pandemic strain to industry. H1N1 vaccine production fell well short of this goal, amounting to only 534 million doses within the six-month milestone, which was reached in December 2009.

Reasons for this trace to lower-than-expected production yields associated with egg-based production methods (H1N1 vaccine yields were two-thirds lower than their seasonal vaccine counterparts). WHO researchers also noted reluctance among some regulatory bodies to approve vaccines with adjuvants (immune system enancing additives) to stretch vaccine doses. Declining H1N1 vaccine demand and requirements for seasonal vaccine production were additional factors.

Flu vaccine production still remains mostly concentrated within a few developed countries and “among seven large manufacturers that are located in the USA, Canada, Australia, western Europe, Russia, China, and Japan.” However, overall vaccine production capacity is expanding. In 2006, vaccine production was centered in nine industrialized countries. At present, influenza vaccine production “is currently available or is being established in 25 countries.”

Within the USA, the President’s Council of Advisors on Science and Technology (PCAST) recently presented a series of recommendations to improve pandemic vaccine production. In the short term, key recommendations included shifting vaccine production from egg-based methods to cell-cultures, improved seed strains and testing as well as larger and more modernized facilities.

Among the longer-term recommendations were support for adjuvenated vaccines, capacity to test and develop vaccines against at least pandemic virus threats, research toward a universal vaccine, and improved guidance from the U.S. Food and Drug and Administration to streamline approvals of new vaccines.

CIDRAP: President’s advisory group looks to speed up flu vaccine
CIDRAP: WHO: Pandemic showed limits of vaccine production capacity

On the international front, H1N1 has receded across much of the world. The World Health Organization (WHO) reports the most active areas of pandemic influenza virus transmission “currently are in parts of the Caribbean and Southeast Asia.” The need to monitor winter influenza developments in the southern hemispere explains the WHO decision to delay consideration of a reduction in pandemic level.

As pandemic H1N1 apparently ebbs, some questions remain for future public health preparedness. Medical research continues to further our understanding of H1N1. The virus itself continues to evolve.

In the USA, public health reponse to H1N1 was a measured success. Public interest in H1N1 remained generally high and receptive to public health messages; the public largely adopted H1N1 prevention recommendations. H1N1 vaccination clincs were erected in “non-traditional venues such as shopping malls, airports, subway stations, and sporting events.” Rates of uptake of seasonal and H1N1 vaccines were impressive. As many as 81 million Americans (up to 27% of the population) were vaccinated against pandemic H1N1.

However, there were vaccine production bottlenecks, due to lower-than-expected vaccine yields, resulting in insufficient vaccine supplies during peak demand in November, 2009, at a time when the pandemic was intensifying. Public health planners can find little comfort in persistent negative perceptions of vaccine safety across large segments of the population. H1N1 resistance to antiviral medications, while still isolated and sporadic, must be closely monitored over time.

In short, the news on H1N1 continues. The focus of this influenza archive going forward, will be on what we have learned, and what we will continue to learn.

Editor’s Note: Apologies to Influenza Monitor readers for the lengthy hiatus.

CDC: 2009-2010 Influenza Season Week 19 ending May 15, 2010
CDC: Updated CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 – April 10, 2010
CIDRAP: H1N1 LESSONS LEARNED: Vaccination campaign weathered rough road, paid dividends
NEJM: The Public’s Response to the 2009 H1N1 Influenza Pandemic
Reuters: WHO panel to review H1N1 pandemic status in coming weeks
WHO: Pandemic (H1N1) 2009 – update 101

Researchers evaulated immune responses in mice after exposing them to several H1N1 viruses (1918, 1940, 1976 and 2009) and found that prior infection with a 1976 H1N1 virus provided complete protection against pH1N1. Mice infected with either 2009 or 1940 seasonal H1N1 viruses showed partial protection from pH1N1.

Comment: A serologic study published in the New England Journal of Medicine (NEJM) indicated substantial pre-existing immunity to pH1N1 in adults aged 60 years and older (34%). pH1N1 immunity for younger adults aged 19-64 was estimated at six percent.

Using a stylized assumption that the 1976 H1N1 vaccine was evenly distributed by age and location, rough calculations suggest approximately seven percent of persons in the 19-64 year age group could have received the 1976 H1N1 vaccine. This is close to the NEJM estimate of preexisting immunity for that cohort.

Hence, the much-maligned 1976 swine flu vaccine appears to have afforded a degree of protection against pandemic H1N1.

Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus

H1N1 vaccine demand is perhaps at low ebb as well. As of 13 Feb, pH1N1 vaccine uptake was estimated around 86 million persons (97 million doses). Despite the safety record of pH1N1 vaccine, which parallels seasonal flu vaccine, surveys continue to indicate persistent public doubts concerning vaccine safety in general.

According to the World Health Organization, pH1N1 transmission persists at elevated levels in areas of Europe and Asia, but is otherwise at declining or low levels in the northern hemisphere. The most active areas of pH1N1 transmission are parts of Southeastern Asia (Thailand and Myanmar) and Eastern Europe (Russia, Bulgaria, Armenia and Moldova). In China, Influenza B is the predominant flu strain in circulation, accounting for 88% of influenza detected in surveillance.

Overall, pH1N1 remains treatable with antiviral medications, oseltamivir and zanamivir. Disagreement remains over the pathogenicity of oseltamivir-resistant mutations of pH1N1 (referred to as D222G/D225G). The Norwegian Institute of Public Health reported that the mutation was associated with 11 of 61 cases of severe illness and was not found in any mild cases. The Influenza Division at the US Centers for Disease Control and Prevention (CDC) countered that global H1N1 data do not show a clear association between the mutation and severe illness, and that the mutation proved fatal in three of eight cases in the USA.

Comment: A comparison of apples-to-apples appears needed. CDC contends the Norwegian data needs to control for covarying factors, such as underlying patient conditions. The three fatalities in the USA that had the mutation were patients treated at Duke University, all of whom had compromised immune systems; this association had not been highlighted in reporting. At most, the Norwegian data suggests an upper-bound on the incidence of this mutation in severe disease. Seasonal H1N1 influenza viruses are now completely resistant to oseltamivir and this is a likely evolutionary path for future pH1N1 mutations.

CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 – January 16, 2010
CIDRAP: CDC – Pandemic vaccine safety record still matches seasonal vaccine
CIDRAP: H1N1 mutation’s proposed link to severe illness debated
LATimes Health: Parents’ vaccination fears remain high
Reuters: Biggest swine flu regret for U.S.: vaccine chaos
WHO: Pandemic (H1N1) 2009 – update 90
WHO: Pandemic (H1N1) 2009 – update 90: Weekly Virological Surveillance Update

CIDRAP: FDA selects pandemic H1N1 for 2010-11 seasonal flu vaccine
WSJ: FDA Panel Recommends Single Flu Vaccine

The committee ruled out a “post-pandemic” phase because, in its view, H1N1 is not yet behaving like normal seasonal infuenza, and that future waves of H1N1 were possible. WHO’s decision will be made public at 1000 GMT on 24 Feb.

Meanwhile, H1N1 has peaked and is waning across the globe. Pockets of “active, but declining H1N1 transmission persist in southern/eastern Europe as well South/East Asia.” Influenza B virus is circulating at elevated levels in China, displacing H1N1. H3N2 is co-circulating at low levels in Asia and China. H1N1 is the predominant strain in the Americas; flu activity in the USA is below baseline.

Last week WHO also recommended that A(H1N1) 2009 replace seasonal (A)H1N1 in the 2010-2011 trivalent seasonal influenza vaccine. As summarized by CIDRAP, the specific WHO recommendations were:

• H1N1 component: a strain similar to A/California/7/2009, replacing A/Brisbane/59/2007
• H3N2 component: a strain similar A/Perth/16/2009, replacing A/Brisbane/10/2007*
• B component: a strain similar to B/Brisbane/60/2008-like virus

* A/Wisconsin/15/2009 is a A/Perth/16/2009 (H3N2)-like virus and is a 2010 southern hemisphere vaccine virus.

Oseltamivir (Tamiflu) resistance in pandemic A(H1N1) 2009 viruses has been limited. However, WHO also noted “the majority of seasonal A(H1N1) viruses were oseltamivir resistant.” This resistance developed during the 2008-2009 flu season.

COMMENT: Flu watchers understandably keep an anxious eye on hot-zone countries like Indonesia, Vietnam and Egypt where H5N1 (avian flu) and H1N1 are in co-circulation, carrying potential for a pathogenic virus reassortment. The WHO report serves as a reminder that a reassortment between 2009 H1N1 and antiviral-resistant seasonal H1N1 viruses would also be an unwelcome development.

CIDRAP: CDC flu barometers show level activity
CIDRAP: WHO picks pandemic strain for next seasonal flu vaccine
Reuters: WHO may declare post-peak pandemic phase next week
Reuters: WHO to decide new flu vaccine formula
WHO: Pandemic (H1N1) 2009 – update 88
WHO: Recommended viruses for influenza vaccines for use in the 2010-2011 northern hemisphere influenza season (PDF)