A Moderate Pandemic with Immoderate Impact ?

Acording to the latest CDC estimates, there have been just over 12,000 deaths from pandemic 2009 H1N1. This stands in contrast to the 36,000 deaths from a typical flu season, a number widely advertised by HHS. This, along with similar fatality rates were observed worldwide, has led some to describe the H1N1 pandemic as “moderate” or even “mild.” But was that really the case ?

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.

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

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Video Digest: H1N1 Retrospective; H1N1 Vaccines Discarded in CA; Weak H1N1 Vaccine Demand in Malaysia



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H1N1 Research: On a “Heading” Toward a Universal Influenza Vaccine

When writing about influenza, it can be difficult to report on cutting-edge research. One has to carefully apply terms like “breakthrough.” One also has to avoid terms like “miracle cure.”

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.

Life Extension - Health And Medical Findings

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


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H1N1 Transitions: Three New H1N1 Variants Detected in India

ProMed mail reports on three new H1N1 variants detected by India’s National Institute of Virology (NIV). All the variants were treatable with the antiviral medication Oseltamivir (Tamiflu). Excerpt and references provided below:

Archive Number 20100525.1741
Published Date 25-MAY-2010
Subject PRO/AH Influenza pandemic (H1N1) (34): Indian variants
A ProMED-mail post


ProMED-mail is a program of the
International Society for Infectious Diseases


Date: Tue 25 May 2010
Source: The Times of India, Pune [edited]


The National Institute of Virology (NIV) here has detected 3 new
variants of the H1N1 virus. Fortunately, all 3 variants have shown
susceptibility to Tamiflu, the drug used in the treatment of swine
flu. However, with the virus actively acquiring new properties, NIV
scientists are apprehensive that it might develop resistance to the
medicines used in treating swine flu. “For now, there is no need to
worry. But we are closely monitoring the virus for any change in its
virulence,” NIV assistant director Sarah Cherian told the Times of
India recently.

Cherian said 7 mutated variants of the virus have been found across
the world so far. “As expected of the seasonal influenza virus, the
H1N1 virus is also going through constant genetic variations which
might lead to significant changes in its antiviral resistance,” she

The variants of the H1N1 virus, representing both recovered and fatal
cases from major cities — Pune, Mumbai, Delhi, Hyderabad and
Bangalore — were analysed at the NIV, and the complete genomes of
these variants were sequenced. The results of the genetic analysis
have been published in the March 2010 issue of the US journal, PLOS

Read the remainder of the article at ProMed Mail

Communicated by:
ProMED-mail Rapporteur Mary Marshall

[The detection of 3 genetic variants circulating in India is an
interesting observation. For the benefit of readers wishing more
precise detail, the abstract of the PLoS ONE paper is posted below.

“Title: Genetic Characterization of the Influenza A Pandemic (H1N1)
2009 Virus Isolates from India. Reference: PLoS ONE 5(3): e9693.

By: Varsha A. Potdar, Mandeep S. Chadha, Santosh M. Jadhav, Jayati
Mullick, Sarah S. Cherian, Akhilesh C. Mishra At: National Institute
of Virology, Pune, India.


PLoS ONE: Genetic Characterization of the Influenza A Pandemic (H1N1) 2009 Virus Isolates from India. Reference: PLoS ONE 5(3): e9693.
Times of India: Pune, 25 May 2010


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H1N1 Lessons: Pandemic Influenza Vaccine Production Capacity: Ready for the Next Pandemic ?

The most significant failure in the global public health response to pandemic H1N1 was the lack of sufficient vaccine supplies in time for the second wave of H1N1.

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.

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CIDRAP: President’s advisory group looks to speed up flu vaccine
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Op-Ed: H1N1 Ebbs Worldwide, Legacies and Lessons Continue

With the passage of time, H1N1 has been quiet in the USA. No states have reported widespread or regional flu activity for five consecutive weeks. Doctor visits for Influenza-like Illness (ILI) are below baseline across all ten CDC regions.

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

H1N1 Update: ELEVATED influenza-like illness (ILI) now reported in CDC Regions 4, 7 and 9

From CDC’s most recent influenza surveillance report, week ending 20 March:

Elevated ILI was seen in Regions 4, 7 and 9. Region 4 is comprised of Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina, and Tennessee. Region 7 is Iowa, Kansas, Missouri and Nebraska. And Region 9 is Arizona, California, Hawaii and Nevada. (Last week, only region 4 had elevated ILI.)

2009 H1N1 Flu: Situation Update – March 26, 2010, 5:30 PM

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NIAID Press Release: Rapid Development of Drug-Resistant 2009 H1N1 Influenza Reported in Two Cases

Friday, March 26, 2010

Media Contact: Anne A. Oplinger
(301) 402-1663

Rapid Development of Drug-Resistant 2009 H1N1 Influenza Reported in Two Cases

Reevaluation of Treatment Strategies for Prolonged Infection Urged

Two people with compromised immune systems who became ill with 2009 H1N1 influenza developed drug-resistant strains of virus after less than two weeks on therapy, report doctors from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Doctors who treat prolonged influenza infection should be aware that even a short course of antiviral treatment may lead to drug-resistant virus, say the authors, and clinicians should consider this possibility as they develop initial treatment strategies for their patients who have impaired immune function.

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ELEVATED influenza-like illness (ILI) activity in CDC Region Four: AL, FL, GA, KY, MS, NC, SC, TN

CDC is reporting ELEVATED influenza-like illness (ILI) activity in Region Four, which includes: Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina, and Tennessee. “Region 4 led the nation at the beginning of the fall wave, which largely followed school openings.” Region 4 also had a higher number of case counts of ILI on college and university campuses than other regions.

Regional influenza activity was reported by three states (Alabama, Georgia, and Mississippi). Local influenza activity has been reported across southern and southeastern states in CDC Regions Four and Five. Recent reports on H1N1 activity from CDC Regions 4 and 5 include:

ATLANTAHealth officials say swine flu hospitalizations in Georgia are up to their highest level since the fall. About 70 to 80 hospitalizations were reported in each of the past two weeks – the most since September, when a large wave of illnesses was hitting the South. (AP – 24 Mar) NOTE: Georgia’s Dept of Community health officially reported 80 and 38 hospitalizations respectively for weeks ending 9 March and 2 March.

MONTGOMERY – Activity reported for last week (March 7-13, 2010) shows the percentage of visits attributed to ILI continues to be elevated in Alabama (7.1%). The baseline set by CDC, above which defines significant influenza activity, in Alabama is 2.0% for the 2009-10 Influenza Season. (ADPH – 18 Mar)

BATON ROUGE – State Health Officer Jimmy Guidry, M.D. announced today that parish health units statewide will host open walk-in H1N1 vaccination clinics this week, as DHH is receiving reports from across that state that hospitals and physician offices have seen an increase in flu-like illnesses in the past few weeks. (DHH – 22 Mar)

Comment: Pandemic H1N1 continues to reach where it can.

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ACHA: ACHA Pandemic Influenza Surveillance: Influenza Like Illness (ILI) in Colleges and Universities: Week Ending March 19. 2010
AP: Swine flu hospitalizations up in GA
AL DPH: Influenza Surveillance in Alabama
GA DCH: H1N1 Hospitalizations and Deaths in Georgia
LA DHH: DHH Launches H1N1 Open Clinic Campaign This Week
MS DH: Influenza-Like Illness Report for 2010, Week 10
Recombinomics: US Wave 3 Start Confirmed By H1N1 Increases in Region 4 Recombinomics Commentary 23:03

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Investigation of Duke University cluster of oseltamivir-resistant H1N1 cases revealed patient-to-patient transmission of H275Y mutation; Health-care professionals had influenza symptoms

A multi-agency team of public health experts recently presented the results of their investigation into the cluster of four immunocompromised patients admitted to Duke University Medical Center over the 21-27 Sep, 2009 timeframe, who were found to have oseltamivir-resistant H1N1 (the H275Y mutation). Three of the patients died.

The investigation involved reviews of patient medical records and infection control measures and interviews with healthcare personnel (HCP) Oseltamivir-resistance was confirmed in virus isolates via serologic and DNA chain-reaction tests, as well as from viral genomic sequencing.

Key excerpts from the report:


“During September 21–27, 2009, four patients were admitted to the hematology ward for reasons unrelated to influenza infection (Figure). All were ambulatory and had opportunity to interact outside their rooms before onset of influenza-related illness. Three patients were located in adjacent rooms. An index patient experienced fever on October 6, 8 days after completing 5 days of oseltamivir prophylaxis following exposure to an ill family member. Isolation precautions were instituted 9 days after symptom onset. The remaining three patients experienced fever or respiratory symptoms 1, 3, and 5 days after the index patient. All four patients were immunocompromised and had concurrent problems that can mimic infection or respiratory illness. Twelve HCPs reported influenza symptoms during the study period; none were tested for pH1N1. Five reported working while ill; one of these received oseltamivir. Viral isolates from the four patients had complete genomic homology and the H275Y mutation for oseltamivir resistance, which was not identified in other pH1N1 specimens obtained from the hospital or throughout the state.”


“Geographic proximity, temporal association of hospital stay, presence of H275Y mutation and genetic homology strongly indicate patient-to-patient transmission of oseltamivir-resistant pH1N1. An index patient experienced oseltamivir-resistant pH1N1 after receiving oseltamivir; however, the source of resistant virus is unknown. Three remaining patients probably acquired oseltamivir-resistant pH1N1 before diagnosis and isolation of this index patient. Transmission by HCPs cannot be established. Diagnosis of pH1N1 is difficult among immunocompromised hosts with complex comorbidities. Although we detected no other cases, increased diagnostic vigilance and aggressive isolation are necessary to limit potential transmission of oseltamivir-resistant pH1N1 among immunocompromised hosts.”

Comment: Available data indicates severely immunocompromised patients make up the plurality of oseltamivir-resistant cases worldwide. It is not clear from this abstract exactly when Duke University Medical Center staff confirmed the H275Y mutation in the cluster of cases. Earlier, the World Health Organization (WHO) had reported “In 3 of the 4 cases, the H275Y mutation was identified before oseltamivir was administered.” Moreover, the abstract does not explore the cause of death among three of the patients, nor any potential connection to “patient-to-patient transmission” of oseltamivir-resistant H1N1.

The Duke University Medical Center press release on the situation stated that:

“Our extensive investigation thus far has revealed that appropriate infection control procedures have been diligently practiced on this isolated unit, and throughout the hospital, and we have experienced no illness among employees taking care of these patients in the affected unit over this period of time.”

The fact that 12 HCPs were symptomatic for influenza, and that five reported working while ill, calls into question the quality of infection control procedures.

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Duke UMC: CDC Confirms Four New Cases of Oseltamivir (Tamiflu)-Resistant H1N1
SHEA: Cluster of Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Among Immunocompromised Patients on a Hospital Ward — North Carolina