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

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

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

http://timesofindia.indiatimes.com/City-Pune/NIV-detects-3-new-variants-of-H1N1-virus-/articleshow/5970862.cms?

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
said.

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
One.

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.
doi:10.1371/journal.pone.0009693
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009693.
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.
ProMed Mail: INFLUENZA PANDEMIC (H1N1) (34): INDIAN VARIANTS
Times of India: Pune, 25 May 2010

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

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:

Results:

“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.”

Conclusions:

“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.

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

Overall pH1N1 has exibited low pathogencity, resulting in approximately 12,000 (estimated) deaths in the US. This is well below the widely quoted figure of 36,000 annual deaths from seasonal flu.

The World Health Organization (WHO) has described pH1N1 as a moderate” pandemic. Many flu experts have never been comfortable with qualitative terms such as “mild” or “moderate”, perhaps in part because they also minimize the import of the disease, and can dissuade publics from taking protective action.

Researchers from the National Institites of Health (NIH) have devised what they term is an “apples-to-apples” methodology to estimate the burden of disease on a population. The metric, termed “Years of Life Lost” (YLL), takes into account the age-distribution of disease-related deaths and extrapolates potential years of life lost across age groups. Expressed as a function, the higher the numbers of deaths, and the lower the mean-age of deaths, the higher is YLL.

NIH researchers describe the impact of pH1N1 as “significant.” By their YLL metric, the burden of p1N1 exceeds that of typical seasonal flu dominated by Influenza A H3N2 virus. NIH research suggests pH1N1 may have had a comparable burden to the (Hong Kong) flu of 1968 (also described as a relatively mild pandemic).

There perhaps is no perfect way to measure the scope, intensity, and duration of a disease outbreak. Numbers of deaths, for obvious reasons, is a metric that is intuitively understood, and of course makes for headlines and optics. While YLL provides a relatively simple metric to compare impacts across pandemics, the measure is still fundametally sensitive to numbers of deaths. Overall, YLL estimates still suggest a moderate burden of disease for pH1N1.

CIDRAP: Study: In life-years lost, H1N1 pandemic had sizable impact
PLoS Currents: Preliminary Estimates of Mortality and Years of Life Lost Associated with the 2009 A/H1N1 Pandemic in the US and Comparison with Past Influenza Seasons

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