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

• US Govt researchers compared the pathogenenicity of pandemic H1N1 in mice with several other viruses to include a reconstructed 1918 virus, a 1976 H1N1 virus, a highly pathogenic H5N1 (avian flu) virus, and a triple reassortment human virus that has been circulating in pigs for at least a decade prior to pH1N1. They found that all “2009 H1N1 viruses replicated efficiently in the lungs of mice and possessed a high degree of infectivity, but did not cause lethal disease or exhibit extrapulmonary virus spread.” 2009 H1N1 “viruses isolated from fatal cases did not demonstrate enhanced virulence in this model compared with isolates from mild human cases.”
• A similar experiment by Dutch researchers compared that pathogenicty of pH1N1 in ferrets with seasonal H1N1 and highly pathogenic H5N1. The results “showed that the new (i.e. pandemic) H1N1 virus causes pneumonia in ferrets intermediate in severity between that caused by seasonal H1N1 virus and by HPAI H5N1 virus. The new (pandemic) H1N1 virus replicated well throughout the lower respiratory tract and more extensively than did both seasonal H1N1 virus (which replicated mainly in the bronchi) and HPAI H5N1 virus (which replicated mainly in the alveoli).”



• Both studies are consistent with earlier research from a team led by Dr Yoshihiro Kawaoka at the University of Wisonsin, Madison, which compared the effects of H1N1 and seasonal in mice, ferrets and monkeys. Their results indicated that the “H1N1 virus (replicated) much more efficiently in the respiratory system than seasonal flu and (caused) severe lesions in the lungs similar to those caused by other more virulent types of pandemic flu.”
• Recent research also led by Dr. Kawaoka engineered 254 combinations of reassorted viruses between a low-pathogenic avian H5N1 and a human seasonal H3N2 strains and subsequently tested a subset of these in mice. Some 96 viruses in this mix were found to be highly replicable. The team tested 75 H5N1 and H3N2 hybrids in mice. Of this group “forty-five viruses were less pathogenic than the avian H5N1 parent, 8 were as pathogenic, and 22 were more pathogenic.” The findings suggested that “human PB2 (gene) is required for the emergence of substantially virulent hybrids.”

No mice, ferrets or monkeys were harmed in the making of this post.

CIDRAP: Study yields highly pathogenic avian, human flu virus mix
J Inf Disease: Severity of Pneumonia Due to New H1N1 Influenza Virus in Ferrets Is Intermediate between That Due to Seasonal H1N1 Virus and Highly Pathogenic Avian Influenza H5N1 Virus
J Virol: Pathogenesis of Pandemic Influenza A (H1N1) and Triple-Reassortant Swine Influenza A (H1) Viruses in Mice.
PNAS: Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence
UW Madison: A new, highly detailed study of the H1N1 flu virus shows that the pathogen is more virulent than previously thought

Background on Chile Earthquake

• USGS: Magnitude 8.8 – OFFSHORE MAULE, CHILE
• AMEMBASSY Santiago: Statement on February 27 Earthquake in Chile
• NOAA: Tsunami Warnings and Advisories
• PAHO: EOC Situation Report #3 – Damage and power shortages force suspension of H1N1 vaccinations

Emergency departments see rise in flu-like illness
Feb 24, 2010 (CIDRAP News), Lisa Schnirring Staff Writer

Some of the nation’s emergency departments are noting increases in flu-like illness cases that appear to be pandemic H1N1, and colleges are reporting the first increase in flu-like illness since the end of November, but it’s not clear if these are early signs of a third pandemic flu wave.

• The American College of Emergency Physicians (ACEP) said today in a Twitter post that some of its members were anecdotally reporting a new wave of pandemic H1N1 patients coming to emergency departments and asked if other physicians were seeing similar patterns.
• Meanwhile, the American College Health Association (ACHA) today reported in its latest surveillance summary of influenza-like illnesses a 52% rise in cases, reflecting the first increase since the end of November. For the week ending Feb 19, the attack rate at schools was 4.1 cases per 10,000 students. The ACHA said some colleges in the southeast and Midwest have reported slight increases in disease activity.
• A spokesman for the Washington State Department of Health said today that pandemic H1N1 cases have slowed but not disappeared, the Associated Press (AP) reported today. Five more people were hospitalized for H1N1 infections over the past week, but no new deaths have been reported. Read the full article.

CIDRAP: Emergency departments see rise in flu-like illness
ACHA Pandemic Influenza Surveillance
AP: Swine flu slows down in Washington state

The research used 846 anonymous, leftover blood samples drawn on hospital and clinic patients from the Pittsburgh area in the mid-November and early December 2009 timeframe. Stored serum samples from 100 healthy, young adults from 2008 were used as a control group.

In addition to pandemic H1N1 (A/California/7/2009), the researchers examined seroprevalences against other virus strains to include: A/Brisbane/59/2007 (a seasonal H1N1 virus), A/Denver/1/1957 (a pandemic H2N2 virus) and A/South Carolina/1/1918 (a pandemic H1N1 virus).

“Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10-19 years having the highest seroprevalence (45%), and persons age 70-79 years having the lowest (5%). The baseline seroprevalence among control samples from 18-24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%.”

The study provided indications of prexisting immunity among seniors exposed to the 1957/1918 pandemic strains as suggested by the high seroprevalences found.

Given these findings, and taking in account H1N1 vaccination efforts (at least 70 million Americans have been vaccinated), the authors conclude “that further sustained viral (pandemic H1N1) transmission is not likely.”

That said, no one is ready to declare an end to the pandemic. According to a panel of experts polled by the Washington Post, influenza “transmission waxes and wanes, and outbreaks of novel pandemic strains occur in particularly unpredictable waves that depend on such variables as human behavior, atmospheric conditions and even competition from other microbes.”

The report further adds “even if there isn’t a third wave, the new H1N1 may well spell the end of one or more of the families of flu virus that have been circulating for decades . That’s what’s happened in previous pandemics, at least.”

CIDRAP: Seroprevalence study shows 21% H1N1 infection rate
PLoS Currents: Seroprevalence Following the Second Wave of Pandemic 2009 H1N1 Influenza
Washington Post: Swine flu wanes, but experts say pandemic strain could reemerge

According to the AP report, WHO’s “emergency committee met Tuesday and suggested it was “premature” to recommend downgrading the global flu outbreak. Swine flu cases have dropped dramatically in recent weeks in Western countries, but the virus has only recently hit Africa. The southern hemisphere is also bracing for another wave of illness in the next few months.”

By WHO protocol, any public announcement is embargoed until after the Director-General informs the 193 member states of the decision. Formal announcement is expected on 24 Feb at 1000 GMT.

AP: WHO: Swine flu still hasn’t peaked
CIDRAP: Novel H1N1 Influenza (Swine Flu): H1N1 Flu Breaking News (23 Feb)

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)

Another study finding was that the “H1N1 virus underwent little antigenic drift in pigs, as shown by the ability of the NJ/76 strain to induce protective immunity in mice against the 2009 H1N1 virus.” The fact that H1N1 influenza virus proteins are antigenically frozen in pigs, make them natural resorvoirs for future pandemics.

This research suggests that the much-maligned 1976 swine flu vaccination effort, which had an uptake of around 40 million Americans, may have conferred some protective effect on the population, in particular for persons aged 35 and up. This is one of the conclusions drawn from a review by Professor Ranaciello in Virology.

Quantifying the extent of this protective effect (in terms of pre-existing immunity) gets a little complicated. An exchange with Professor York, who pens Mystery Rays from Outer Space, (MRFOS) suggests some protective effect from the 1976 vaccines exists, but that it should not be overstated.

A study published last year in the New England Journal of Medicine (NEJM)assessed levels of pre-existing immunity to 2009 H1N1 to be 4% in children, 6% in young adults and 34% in older adults (those born before 1950). Assuming the 1976 vaccine was proportionally distributed by age, rough calculations suggest 7% (13 million persons) of the present day young adult cohort (aged 19-64) could have pre-existing immunity from the 1976 vaccine, close to the 6% estimate in NEJM.

However, the hard part is reconciling similar patterns of immunity to H1N1 observed elsewhere in the world among populations who had no access to the 1976 vaccine.

MRFOS estimates that current immunity to H1N1 in the US is in the range of 49-52%. These projections take into account estimated H1N1 vaccine uptake (80 million) and H1N1 infection rates (55 million) and adjusts for potential overlap between both. This level of immunity augurs well against a winter wave of H1N1.

CDC: Emerging Infectious Disease Volume 15, Number 11–November 2009, Letter, Preexisting Immunity to Pandemic (H1N1) 2009
MRFOS: How many Americans are immune to H1N1?
NEJM: Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus
PLoS Pathogens: Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines
Virology: Protection against 2009 influenza H1N1 by immunization with 1918-like and classical swine viruses