PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

[Shiloh]

Source: http://www.forbes.com/forbeslife/health/feeds/hscout/2008/10/29/hscout620736.html

Flu Vaccine Could Prevent 357,000 Deaths in Pandemic
10.28.08, 8:00 PM ET

WEDNESDAY, Oct. 29 (HealthDay News) -- Vaccinating infants with what's known as the "7 valent pneumococcal conjugate vaccine" (PCV7) could save more than 357,000 lives and $7 billion in costs by preventing bacterial infections during a flu pandemic, according to a predictive model developed by U.S. researchers.

Pneumococcal disease (such as meningitis) and other bacterial infections can follow flu and cause secondary infections that worsen flu symptoms and increase the risk of flu-related death. For example, it's believed that bacterial infections caused almost half of the deaths of young soldiers during the 1918 worldwide flu pandemic, according to background information in an Emory University news release.

"We've known for years that bacterial infections can develop after influenza. Unlike the 1918 flu pandemic, which preceded the antibiotic era, we now have vaccines that can prevent these types of pneumococcal infections. This model shows what a dramatically different outcome we could expect with standard PCV vaccination," Keith P. Klugman, professor of global health at Emory's Rollins School of Public Health, said in the news release.

He and colleagues at Harvard University, i3 Innovus in Medford. Mass., and Wyeth Research created a model to estimate the public health and economic effect current influenza vaccination practices would have on children younger than two years old during a flu pandemic. Since 2000, the Centers for Disease Control and Prevention has recommended PCV vaccinations for infants and children.

The model showed that current PCV vaccination practices lower costs in a typical flu season by $1.4 billion and would cut costs by $7 billion in a pandemic. It also predicted that PCV vaccination would prevent 1.24 million cases of pneumonia and 357,000 pneumococcal-related deaths in a pandemic.

The findings were presented this week at an infectious diseases conference in Washington, D.C.

"Our research shows that routine pneumococcal vaccination is a proactive approach that can greatly reduce the effects of a future flu pandemic," Klugman said. "Countries that have not yet implemented a pneumococcal vaccination program may want to consider this as part of their pandemic flu preparedness."

Klugman is a paid consultant for Wyeth Pharmaceuticals, which funded the study.

More information

The Immunization Action Coalition has more about pneumococcal diseases.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

.....predicted that PCV vaccination would prevent 1.24 million cases of pneumonia and 357,000 pneumococcal-related deaths in a pandemic.

If I'm understanding the genetics correctly - if H5N1 maintains it's polybasic cleavage site (if/when it goes pandemic) it would be pantropic, so there would be many deaths unrelated to pneumonia. Using models based on 1918 isn't giving us an accurate picture.

Have any public presentations included the implications of a pantropic influenza?

.

 

[mixin]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Discussion of pantropic influenza was before my flubie days. I found this explanation from someone named WatchfulBabbler, Oct '05:

H5N1 is especially problematic because it is theoretically pantropic. Imagine the flu virus as a biological beartrap that can be activated only by a certain protein, tryptase clara. When the virus encounters tryptase clara in the lungs, the precursor HA0 is turned into hemagglutinin, or HA (the "H" in "H5N1" -- the numbers indicate antigen types for the hemagglutinin and neuramidase proteins). HA is responsible for target cell recognition through sialic acid binding, and for fusing with the target cell's lipid membrane (accomplished through a pH-mediated coformational change). So the key for viral infection in influenza is the "triggering" of the hemagglutinin spike through the cleavage site.

H5N1 has what's termed a "polybasic cleavage site," which can be activated by a wider array of proteins -- including furin, a ubiquitous protease. So H5N1 is theoretically pantropic -- capable of growing throughout the body, rather than only in the lungs as in pneumotropic influenza. Most H5N1 isolates have been shown to be pneumo- and neurotropic (the HA can bind to the sialic acid in the gangliosides of neural cells).

http://hotlineblog.nationaljournal.com/archives/2005/10/bush_dodges_a_q.html

 

[Giuseppe]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Yet the H5N1 neuroinvasion isn't proven, at least in some of the cases when necropsies were conducted.

The gross pathologic changes are in lungs with induction of acute respiratory distress syndrome, multi-organ failure (due in part to coagulopathy and diffuse intravascular coagulation, trombosis, haemorrhages).

It may be useful to recall the study about the 2007 familiar cluster of human cases where an extensive review of anatomo-pathological findings was presented for the fatal case.

If the H5N1 efficient spreads via bloodstream and infects other organs remains to be established as cause of the high case fatality rate.

However, a primary clinical presentation with gastro intestinal symptoms is also recorded but the main cause of death remains the ARDS.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

....multi-organ failure (due in part to coagulopathy and diffuse intravascular coagulation, trombosis, haemorrhages).

Interesting that there are multiple causes for multi-organ failure.

If memory serves me correctly, H5N1 can be activated by plasminogen. Wouldn't that be sufficient to also cause multi-organ failure?

In the Sumatran Karo cluster, the surviving male suffers from effects of H5N1-caused encephalitis? Was that from cleavage by spinal fluid, or another pathogen?

Could you supply a link to the 2007 study referenced?

.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Here are some previous threads that discussed lethality related to polybasic cleavage site & what enzymes, etc. caused cleavage:

http://www.flutrackers.com/forum/showthread.php?p=42499&highlight=plasminogen#post42499

http://www.flutrackers.com/forum/showthread.php?p=42499&highlight=plasminogen#post42499

http://www.flutrackers.com/forum/showthread.php?t=13840&highlight=plasminogen


It was also discussed that experimental A/WSN/33. Dr. Niman discussed this at:
http://www.recombinomics.com/News/12040402/1933_2004_H1N1.html

PNAS discussed the impact of plasminogen binding at:
http://www.pnas.org/content/97/12/6785.full

 

[Giuseppe]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Interesting that there are multiple causes for multi-organ failure.

If memory serves me correctly, H5N1 can be activated by plasminogen. Wouldn't that be sufficient to also cause multi-organ failure?

In the Sumatran Karo cluster, the surviving male suffers from effects of H5N1-caused encephalitis? Was that from cleavage by spinal fluid, or another pathogen?

Could you supply a link to the 2007 study referenced?

.

An excerpt from NEJM: n engl j med 358;3 www.nejm.org january 17, 2008
(...)
Viral Factors
The viral and host factors that determine host-restriction and disease manifestations are incompletely understood.38

Preferential binding of the influenza A (H5N1) virus to α2,3-linked sialic acid
receptors on avian cells39 is thought to be key in preventing influenza A (H5N1) and other avian influenza viruses from readily infecting humans.

Some influenza A (H5N1) viruses isolated from humans have acquired mutations that permit binding to both α2,3-linked sialic acid receptors and α2,6- linked sialic acid receptors,40 but these mutations appear to be insufficient for efficient human-tohuman transmission.

To date, influenza A (H5N1) viruses have shown no transmissibility or poor
transmissibility between ferrets and between swine, and reassortment between an influenza A (H5N1) virus and an influenza A (H3N2) virus did not confer transmissibility in ferrets.41

Changes in multiple viral genes are probably required to generate a potentially pandemic influenza A (H5N1) virus.

All recent influenza A (H5N1) viruses retain a polybasic amino acid motif at the HA1?HA2 connecting peptide that is characteristic of highly pathogenic avian influenza viruses.

Geographic variations in this motif have not been associated with obvious changes in the virulence of infection in humans.

Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and replication at temperatures present in the upper respiratory tract (Fig. 1).42

However, these mutations do not correlate with obvious differences in mortality among humans with this viral infection.3,21

Viral Replication
The primary pathologic process that causes death is fulminant viral pneumonia.

The target cells for replication of the influenza A (H5N1) virus include type 2 alveolar pneumocytes and macrophages. 17,43,44

Bronchiolar and alveolar cells, but not epithelia from the trachea or upper respiratory tract, express detectable α2,3-linked sialic acid receptors.
43-45

However, influenza A (H5N1) viruses replicate in ex vivo organ cultures of the upper respiratory tract,44 postmortem studies show virus in tracheal epithelia,17,46 and high titers of virus are detectable in specimens of throat and tracheal aspirates from humans infected with influenza A
(H5N1) virus.3

These findings suggest that the initial infection may occur in either the upper or lower respiratory tract, although the latter may support more efficient replication.

Limited data show that patients with influenza A (H5N1) disease may have detectable viral RNA in the respiratory tract for up to 3 weeks, presumably because of negligible preexisting immunity and possibly viral evasion of immune responses. 3

One patient with fatal infection treated with both antiviral agents and corticosteroids had viral antigen and RNA in tracheal samples on day 27 after the onset of illness.17

Viral loads in the pharynx are higher and plasma viral RNA is detected more often in patients with fatal disease than in those with nonfatal disease, indicating that levels of viral replication influence the outcome. 3

The reported presence of infectious virus in the blood, cerebrospinal fluid, or viscera of several patients with fatal disease indicates that, as in birds and several mammalian species, disseminated infection occurs in some humans.3,17,36,37,46

A fatal influenza A (H5N1) infection in one pregnant woman who received corticosteroids for treatment of the disease was associated with virus
infection of the brain, placenta, and fetus.17

Infectious virus and viral RNA have been detected in feces and intestines, suggesting that the virus sometimes replicates in the gastrointestinal tract.1,3,36,37,46

Pathological Findings
The few reported autopsies of patients with influenza A (H5N1) virus infection have shown diffuse alveolar damage with hyaline membrane formation, patchy interstitial lymphoplasmacytic infiltrates, bronchiolitis with squamous metaplasia, and pulmonary congestion with varying degrees of hemorrhage.17,46,47

Acute exudative, diffuse alveolar damage with macrophages, neutrophils, and activated lymphocytes has been detected in patients who died within 2 weeks after the onset of illness.

Apoptosis in alveolar cells and infiltrating leukocytes are prominent findings.46 Lymphocyte depletion occurs in the spleen, lymph nodes, and
tonsils; histiocytic hyperplasia and reactive hemophagocytosis presumably result from host cytokine responses and viral infection. Edema and degeneration of myocytes in the heart and extensive acute tubular necrosis in the kidney have been observed.

Host Responses
Higher plasma levels of macrophage and neutrophil- attractant chemokines and both proinflammatory and antiinflammatory cytokines (interleukin-
6, interleukin-10, and interferon-γ) have been observed in patients with influenza A (H5N1) virus infection ? particularly in patients with fatal
infection ? than in patients with conventional influenza.
3 Plasma levels of cytokines and chemokines correlate positively with pharyngeal viral loads,3 suggesting that these responses are driven
by high-level viral replication. In vitro experiments involving primary human macrophages and lung pneumocytes show differential up-regulation of
multiple cytokines by influenza A (H5N1) virus as compared with human influenza viruses,48 indicating that viral hyperinduction probably contributes to hypercytokinemia.

In mouse models of influenza A (H5N1) virus infection, mice with deficient induction of interleukin-6, macrophage inflammatory protein 1α, or tumor necrosis factor α or its receptors49,50 and mice treated with lucocorticoids,50 had similar mortality as compared with wild-type animals;
mice without interleukin-1 receptors had increased mortality.49 Tissue damage in human influenza A (H5N1) disease probably results from
the combined effects of unrestrained viral infection and inflammatory
responses induced by influenza A (H5N1) infection. Knowledge of the
mechanisms of hypercytokinemia is insufficient to guide safe, rational immunomodulatory treatment at present.

Clinical Features
Currently, illness due to influenza A (H5N1) viruses typically manifests as severe pneumonia that often progresses rapidly to the acute respiratory distress syndrome.

The time from the onset of illness to presentation (median, 4 days) or to
death (median, 9 to 10 days) has remained unchanged from 2003 through 2006 (Table 1).16 Observed differences in mortality among patients
with presumed clade 1 and clade 2 virus infections (Tables 1 and 2)1,21,24,35,51 are difficult to interpret because of variations in medical practices and the time from the onset of illness to treatment among affected countries.

Febrile upper respiratory illnesses without pneumonia in children have been reported more frequently since 2005.20,21 Early consultation and antiviral therapy may have altered the clinical
course of these illnesses.

Less frequent gastrointestinal symptoms have been reported since 2005 (Table 2), suggesting that some manifestations of clade 1 and 2 virus infections may differ from each other. Leukopenia, lymphopenia, mild-tomoderate thrombocytopenia, and elevated levels of aminotransferases are common but not universal (Table 2). Lymphopenia and increased levels of lactate dehydrogenase at presentation have been
associated with a poor prognosis.1,3,21,37 Other reported abnormalities include elevated levels of creatine phosphokinase, hypoalbuminemia, and
increased d-dimer levels and changes indicative of disseminated intravascular coagulopathy.20,21

The nonspecific clinical presentation of influenza A (H5N1) disease has often resulted in mis- diagnosis of subsequently confirmed cases (Table
3); influenza A (H5N1) virus infection has been suspected in only a small number of patients.

Health care staff should include influenza A (H5N1) virus infection in the differential diagnosis for patients who present with epidemiologic
risk factors and unusual courses of illness, especially rapidly progressing pneumonia (see Fig. 2 of the Supplementary Appendix).
(...)

www.nejm.org on January 17, 2008 .
-
-----

 

[Giuseppe]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

CIDRAP >> Benefits of flu vaccination hotly debated

Benefits of flu vaccination hotly debated

Maryn McKenna * Contributing Writer
Oct 30, 2008 ? WASHINGTON (CIDRAP News) ?

The benefits conferred by influenza vaccination?to recipients and to their close contacts?were hotly disputed at an international medical meeting this week.


Presenters at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy and the 46th annual meeting of the Infectious Diseases Society of America (ICAAC-IDSA) presented abundant but often contradictory evidence regarding flu vaccine's direct and indirect protective abilities.

The question whether flu vaccine protects recipients both from developing flu and from serious complications of flu, as well as whether its administration protects contacts of recipients, has been an active research topic over the past year.

A study published earlier this month in the New England Journal of Medicine (and placed online in September) found that giving the flu shot to pregnant women lowered both their risk of flu and also the risk for their newborns, who were too young to be vaccinated themselves.

Reports in the American Journal of Respiratory and Critical Care Medicine in September and the Lancet in August contended that flu vaccine's ability to protect the elderly from death and from pneumonia has been overstated, and several papers have pointed out that, while vaccination in the elderly has increased, the mortality rate has not declined.

Flu vaccine came in for additional critical examination during ICAAC-IDSA, which drew 15,000 people to Washington, DC, and concluded Oct 28.

Observational studies faulted
"Observational studies have greatly exaggerated vaccination benefits in the elderly," Lone Simonsen, PhD, of George Washington University said Tuesday afternoon (Oct 28). She wrote a controversial paper challenging flu-mortality estimates for the elderly in 2005 while serving as a National Institutes of Health senior scientist.

Such studies distort reality, she said, by assigning any deaths in winter to flu?including deaths that occur before the flu season begins?and do not make sense given what is known about age-related decay of the immune system. She proposed that flu researchers tackle the problem of making separate, more immunogenic vaccine formulas for seniors, and stressed the importance of indirect protection via vaccines given to child and adult contacts of the elderly.

But vaccinating children to protect others was challenged in a separate presentation, with Catherine Weil-Oliver of the Universite de Paris arguing that indirect benefit "has not been demonstrated in schoolchildren in any European study. . . . In children younger than two, no indirect benefit has been recorded at all.

"Looking to flu vaccine to prevent death among the elderly may be focusing on the wrong benefit, Dr. Kristin Nichol of the University of Minnesota said Tuesday. While studies of reductions in mortality may have been clouded by selection bias, she said, studies that show decreases in rates of respiratory diseases and hospitalizations look solid.

"We need to remember that the vaccine also reduces influenza illness and it reduces hospitalization, and so while we explore the controversy we need to continue to vaccinate the elderly," she said.

Age and immunization rates
A poster presentation earlier in the conference explored one of the hypotheses behind the distrust of flu-mortality studies: that they are subject to a "healthy recipient" design defect. Several Kaiser Permanente researchers looked at medical records for recipients of flu vaccine older than 65 who are members of Kaiser Permanente of Northern California, a healthcare organization with about 3 million members.

They found a statistical oddity: The likelihood of an elderly person's taking the flu shot rose along with their age and risk of flu mortality, but only up to a certain age. Once women passed 80 and men passed 85, they stopped taking the shot, even though their risk of dying from flu complications continued to rise.

The authors theorized that the very old are so frail that they are unable to get the shots by themselves, while attendants or healthcare workers deem the shot not useful for them. The result, the authors said, is that the oldest old and most at risk from flu complications are excluded from analyses of flu-shot effectiveness and age, so that results are distorted. (Baxter R, Fireman B, Lee J. "Who gets flu vaccines? A look at bias in flu vaccine effectiveness studies" [Abstract G1-1206])

Meanwhile, however, other age-groups for whom the flu vaccine is most recommended continue to go unvaccinated.

That includes children, according to a team from the Centers for Disease Control and Prevention (CDC), Vanderbilt University, and the University of Rochester. They examined the medical histories of 772 children younger than 5 and 401 children aged 5 to 12 who were brought to outpatient care for flu-like symptoms and fever. Among the older children, 133 had at least one characteristic that put them at high risk for serious flu complications, but only 32 of them (24%) had gotten a flu shot. Among the younger children, 549 had at least one high-risk indication, but only half?275 or 51%?had gotten at least one dose of flu vaccine. (Shinde V, Iwane M, Prill M, et al. Influenza among outpatient children: US, 2006-07. [Abstract G1-1700])

The concern about low immunization rates also includes pregnant women.

An analysis from Bridgeport Hospital and Yale University Medical School in Connecticut found that, out of 520 women who were pregnant during flu season, 19% had been vaccinated, though 28% had discussed vaccination with their physicians during prenatal care. (Panda B, Stiller R, Bruce L, et al. Influenza vaccination in pregnancy: compliance with current CDC guidelines for prevention and control of influenza pertaining to vaccination during pregnancy. [Abstract K-4202])

And healthcare workers also continue to have low vaccination rates.

Researchers from the Chinese University of Hong Kong reported that among 133 acute-care nurses who responded to a questionnaire, 38% said they had received flu vaccine?but 23% of the group developed flu-like illness themselves, and most missed work as a result. (Ng K, Lee N, Hui D. A Survey on ILI among health-care workers during a peak 'flu' season ? What are the risk factors? [Abstract K-4204])

The answer to improving protection against flu and flu complications, one group of scientists said, might be an additional vaccine?and not just for ordinary seasons, but for an influenza pandemic as well.

Researchers from Emory University and the biotech companies i3 Innovus and Wyeth Research modeled the potential effect of vaccinating infants during a flu season with Prevnar, the 7-valent pneumococcal conjugate vaccine, in hopes of preventing the secondary bacterial infections that frequently cause flu-season deaths.

They found that in a typical flu season, preventing post-flu bacterial pneumonia saves $1.4 billion in healthcare spending. In a flu pandemic such as 1918, however, vaccination's effect would be much larger: It would prevent 1.24 million cases of pneumonia and 357,000 pneumococcal-related deaths and reduce costs by $7 billion. (Rubin JL, McGarry LJ, Klugman KP, et al. Public health and economic impact of 7-valent pneumococcal conjugate vaccination in an influenza pandemic in the US. [Abstract K-4210])
-
​

<cite cite="http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/oct3008debate.html">CIDRAP >> Benefits of flu vaccination hotly debated</cite>

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Thanks for the information in #7 above.

.

 

[mixin]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

From IOH's post: "The primary pathologic process that causes death is fulminant viral pneumonia." Now, do they really mean viral pneumonia? As I understand, our v.p. typically is not very severe and usually doesn't require treatment.

I find it strange that the H5N1 is in the lungs but no bacterial pneumonia is found; they don't vax for it over there, do they? I would assume they have the same types of pneumococcal-related complications that we have.

Then, I wonder why disseminated infection occurs in some humans and virus sometimes replicates in the gastrointestinal tract. If these patients somehow ingested the virus, would that account for infection in those places?

 

[Giuseppe]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

From IOH's post: "The primary pathologic process that causes death is fulminant viral pneumonia." Now, do they really mean viral pneumonia? As I understand, our v.p. typically is not very severe and usually doesn't require treatment.

I find it strange that the H5N1 is in the lungs but no bacterial pneumonia is found; they don't vax for it over there, do they? I would assume they have the same types of pneumococcal-related complications that we have.

Then, I wonder why disseminated infection occurs in some humans and virus sometimes replicates in the gastrointestinal tract. If these patients somehow ingested the virus, would that account for infection in those places?

It seems that actual genetic structure of the H5N1 HA does permit the virus to replicate very efficiently when introduced in the human body: the huge number of virions, coupled with the capability of attack several cells lines outside upper and lower respiratory tract and the immune system disregulation achieved by this virus, results in a severe condition and eventually in the high case fatality ratio.

Further, H5N1 NA (neuraminidase) causes efficient virions detachment from host cells and thus more of these virions are free to circulate into extracellular fluids.

It is possible that a fraction of these virions reaches the bloodstream and by this way, would be dispersed toward other organs.

However, the primary 'target' remains lungs.

Incidentally, infections could be develop into other organs via bloodstream or ingestion of lungs excreta, or via primary introduction of viruses by contaminated material (uncoocked food, raw eggs with contaminated surfaces by birds faeces...)

We have perhaps a virus with multi-organ infection capability but this event (non-respiratory infections) is nonetheless rare when compared with lungs invasion.

If other pathogens are involved in the poor outcome of H5N1 human infection remains to be established as necroscopic examinations conducted to date are very few.

It is also possible that microbiological examination fail to isolate bacterial organisms due to poor quality of samples or bad conservation of them.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

...... As I understand, our v.p. typically is not very severe and usually doesn't require treatment......

I had pneumonia from H2N2 in 1957 & spent a miserable (despite antibiotics) month in bed! Don't discount effects of even a novel antigen influenza.

.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Regarding plasminogen's impact on cleavage, I quote Dr. Taubenberger....
--------------------------------------
Influenza virus hemagglutinin cleavage into HA<SUB>1</SUB>, HA<SUB>2</SUB>: No laughing matter

1. Jeffery K. Taubenberger*

+Author Affiliations

1. <ADDRESS>Division of Molecular Pathology, Department of Cellular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000 </ADDRESS>

What do an odd lab-derived strain of influenza, fowl plague virus, and the 1997 Hong Kong chicken flu have in common? The answer lies in how, and more specifically by what protease, the hemagglutinin protein of these various influenza strains is cleaved for viral activation. What does this have to do with the most devastating influenza virus of them all, the 1918 ?Spanish? influenza? The connection may be a new and interesting mechanism for hemagglutinin cleavage proposed by Goto and Kawaoka in an article in this issue of Proceedings (1).

In a series of experiments confirming and synthesizing 25 years of experimental data (2?4), Goto and Kawaoka (1) demonstrate specifically how the neuraminidase (NA) protein of influenza A/WSN/33 (H1N1), a curious variant of the first human influenza virus ever isolated, mediates hemagglutinin (HA) cleavage. Goto and Kawaoka (1) provide evidence for a model whereby the NA of WSN/33 directly binds plasminogen, sequestering it for cleavage activation. Subsequently, active plasmin cleaves and activates influenza hemagglutinin. Being able to sequester plasminogen for hemagglutinin cleavage allows the influenza virus to infect cells other than its usual targets.

With the exception of WSN/33 and the few influenza strains named above, most influenza viruses replicate in a strictly limited subset of cells. Influenza A viruses are negative-stranded RNA viruses. Like many other enveloped viruses, they code for a surface glycoprotein that must be cleaved by cellular proteases for activation. HA, a major influenza surface glycoprotein, is translated as a single protein, HA<SUB>0</SUB>. For viral activation, HA<SUB>0</SUB> (assembled as trimers) must be cleaved by a trypsin-like serine endoprotease at a specific site, normally coded for by a single basic amino acid (usually arginine) between the HA<SUB>1</SUB> and HA<SUB>2</SUB> domains of the protein. After cleavage, the two disulfide-bonded protein domains produce the mature form of the protein subunits as a prerequisite for the conformational change necessary for fusion and hence viral infectivity (5).

Influenza is a zoonotic disease, infecting a wide variety of warm-blooded animals, including birds and mammals. In aquatic birds, normal influenza replication takes place in the intestinal tract and tends not to cause symptoms. In mammals like humans and swine, influenza replication is limited to epithelial cells of the upper and lower respiratory tract. This tissue tropism is controlled to some extent by the limited expression of the appropriate protease for viral activation (6). In mammals, the suspected protease in the respiratory tract is tryptase Clara, a serine protease produced by nonciliated Clara cells of the bronchial and bronchiolar epithelia (6).

Occasional avian influenza strains have been described with an insertion mutation at the cleavage site of HA, allowing HA to be cleaved by ubiquitously expressed proteases (furin and other subtilisin family proteases) (6). As a consequence, the virus can replicate throughout the bird?s body, producing necrotic foci in spleen, liver, lung, and kidney and encephalitic lesions in brain (7). These highly virulent strains have been observed in only two of the 14 described HA subtypes in birds (6) and include those influenza strains previously described as fowl plague viruses. They emerge only occasionally but can cause devastating mortality in poultry flocks (8).

The insertion responsible for the ubiquitous cleavage adds additional basic amino acids at the cleavage site (9), with a minimal motif of R/L-X-R/L-R. Until recently, this mutation had been found only in avian viruses of the H5 and H7 subtypes, subtypes that were not thought to infect humans. This barrier was broken dramatically in 1997 in Hong Kong when 16 people were infected with an avian H5N1 influenza virus (10). Five people died of complications of infection, including the index case, a 3-year-old child who died with Reye?s syndrome (11). The A/Hong Kong/156/97 (H5N1) virus isolated from the 3-year-old child possessed the cleavage site mutation typical of virulent avian influenza viruses (12, 13). Of the 12 patients clinically described (11), seven had pneumonia and/or acute respiratory distress syndrome. Gastrointestinal symptoms and impaired hepatic and renal function also were described. Whether the cleavage site mutation in these cases gave the virus the tissue pantropicity it showed experimentally in chickens (12) is not known, and definitive viral replication outside the respiratory tree in these patients was not observed (11).

Nevertheless, it may be that the cleavage site mutation in these cases contributed to the lethality of the virus.

Although the HA cleavage site mutation had not been found previously in humans, an influenza strain with the ability to replicate outside its normal host cells was described >50 years ago. WSN/33 was produced in 1940 by forcing the parent strain, WS/33, to replicate in mouse brain (14) to develop an animal model for the observed neurologic complications associated with the 1918 influenza. The strain was passaged extensively in ferrets, in chicken eggs, in mouse lung, and finally in mouse brain. Although this strain was believed initially to be specifically pneumotropic and neurotropic, producing a lethal encephalitis in mice, it recently has been shown to be pantropic or capable of systemic infection in mice (15).

This leads us back to the paper by Goto and Kawaoka in this issue of Proceedings (1). They describe a functional model of how the HA protein of WSN/33 is cleaved more readily, synthesizing data from experiments going back over 25 years. One of the unusual properties of WSN/33 is its ability to undergo HA cleavage activation in tissue culture without the addition of exogenous trypsin. As early as 1973, Lazarowitz, et al. (2) were able to explain this observation with the finding that WSN/33 had its HA cleaved by serum plasmin. They demonstrated that, in the absence of serum or in plasminogen-free serum, no HA cleavage occurred. Schulman and Palese (3) showed that the NA protein of WSN/33 was a necessary component for HA cleavage, and in 1993, Li et al. (4) found that the NA of WSN/33 lacked a crucial glycosylation site at residue 146 (residue 130 for WSN/33, which has an in-frame 48 base deletion). Restoration of this glycosylation site by reverse genetics yielded a mutant WSN/33 virus that could not undergo replication in tissue culture without exogenous trypsin. What the above papers lacked was a coherent model to synthesize these observations. The current study describes a model whereby plasminogen binds specifically to the NA of WSN/33. In so doing, the WSN/33 NA sequesters plasminogen on the cell surface so that it can be activated. Once activated, plasmin, also a serine protease, recognizes the single arginine motif at the cleavage site and cleaves HA<SUB>0</SUB> into HA<SUB>1</SUB> and HA<SUB>2</SUB>.

The NA of WSN/33 differs from the NA of its parent strain, WS/33, by >1 dozen amino acids. However, Goto and Kawaoka show convincingly that one key difference accounts for the ability of WSN/33 NA to bind plasminogen. The change is at the previously identified loss of a glycosylation site (4) at residue 146 (N2 numbering). The N146R change in WSN/33 alters the N-X-S/T motif necessary for posttranslational glycosylation of NA (4). In a revealing experiment, they produced a mutant NA of the parent virus, WS/33, lacking the conserved glycosylation site by substituting an arginine for asparagine (recreating the WSN/33 sequence at that site). Significantly, this NA also bound plasminogen.

Goto and Karaoka (1) also show that an amino acid shared between WS/33 and WSN/33, the carboxyl-terminal lysine at residue 453, is also necessary for plasminogen binding. The carboxyl-terminal lysine is a feature common not only to WS/33 and WSN/33 but is a general feature of NAs of the N1 subtype. In their study, K453R or K453L mutants of WSN/33 also lost the ability to bind plasminogen. Finally, they were able to demonstrate plasminogen binding to WSN/33 NA by flow cytometry. WSN/33 NA was expressed on the surface of 293T cells. The cells were incubated with plasminogen and detected with an anti-human plasminogen antibody. Plasminogen binding was not observed with the K453R mutant of WSN/33 nor with cells expressing the NA of A/Hong Kong/68 (H3N2).

WSN/33 initially was developed in a series of experiments designed to produce a neurovirulent influenza virus, and it is now known that enhanced HA cleavability conferred by WSN/33 NA is related to its neurovirulence. However, convincing in vivo and in vitro experiments by Sugiura and Ueda (16) and Nakajima and Sugiura (17) demonstrated that WSN/33 neurovirulence required the matrix (M) and nonstructural (NS) segments in addition to NA. Reassortant viruses containing only NA derived from WSN/33 could not produce lethal encephalitis in immunocompetent mice. Genes from WSN/33 M and NS segments seemed to act as accessory virulence factors to enable efficient viral replication. Reassortants without WSN/33 NA demonstrated uncleaved HA as would be expected given the model of Goto and Kawaoka (1). What these experiments show, however, is that the biological behavior of neurovirulence is polygenic and cannot be fully explained by potentially pantropic HA cleavage alone.

Whereas Goto and Kawaoka?s model (1) is based on a laboratory-derived influenza strain, the broader question raised by their work is the role enhanced HA cleavability or altered tissue tropism may play in the virulence of naturally arising human influenza strains. The 1918 ?Spanish? influenza virus caused a pandemic, killing 20?40 million people. It killed an unusually high number of young healthy adults (18). Although most deaths were the consequence of secondary bacterial pneumonias (there were no antibiotics available in 1918), a subset died in just a few days with massive pulmonary hemorrhage or edema. Was the lethality of the 1918 influenza a result of enhanced hemagglutinin cleavability? After the cleavage site mutations were characterized in lethal avian H5 and H7 strains, it was suggested that the 1918 strain may have possessed a similar HA cleavage site mutation (19). Because no viral isolates were made during the pandemic, this virus was thought to be lost for direct analysis. In 1997, however, small fragments of viral RNA were obtained for sequence analysis from an autopsy sample of a victim of the 1918 influenza. The initial characterization of the virus confirmed the H1N1 subtype and demonstrated that the 1918 HA did not possess the cleavage site mutation seen in the lethal H5 and H7 viruses (20). This finding eliminated the HA cleavage site mutation as an appealing explanation for the virulent behavior of the 1918 virus.
Perhaps, however, as Goto and Kawaoka (1) suggest, the WSN/33 model of influenza viral activation will help explain the virulence of the 1918 strain. Intriguingly for this hypothesis, the small fragment of the 1918 NA reported last year (20) was a perfect match for WSN/33. Because the 1918 HA did not have the cleavage site mutation, an examination of its NA gene for the N146R change of WSN/33 and for the carboxyl-terminal lysine residue important in plasminogen binding will be very interesting.
The feature described by Goto and Kawaoka (1) only has been observed in a laboratory-derived influenza strain and not in a wild-type virus, so it remains to be seen whether their model of HA cleavage would indeed confer enhanced pathogenicity or tissue pantropicity to a virus other than WSN/33. Does the NA change confer plasmin cleavability on all HAs or just the HA of WSN/33? Conformational differences other than the basic amino acid(s) in the cleavage site can effect protease activity.

The glycosylation pattern of HA already has been shown to be critical for cleavage activation in at least one case (19). Furthermore, NA-mediated HA cleavability is necessary but not sufficient for neurovirulence. What other gene changes are present in WSN/33 that give it the ability to cause lethal murine encephalitis? The reassortant viruses described by Sugiura and Ueda (16) suggest that the WSN/33 M and NS segments also are needed to confer neurovirulence. What are the specific changes in these genes? Of interest, Francis and Moore (14) were only able to produce this neurovirulent strain in 1940 by using the parent virus WS/33. All attempts to produce neurovirulent variants of Sw/Iowa/15/30 and PR/8/34 were unsuccessful (14). What accounts for the failure of these related strains to adapt to mouse brain? Finally, is WSN/33 just an unusual laboratory-derived strain, or does it recapitulate genetic and functional features of the 1918 virus?

WSN/33 and another independently derived neurovirulent derivative of WS/33, NWS/33 (21), were produced almost 60 years ago to model the unusual neurologic sequelae reported during the 1918 pandemic. Most notable among these was the coincident pandemic of encephalitis lethargica and postencephalitic Parkinsonism described by von Economo (22). Despite intensive efforts, no causal link between influenza and encephalitis lethargica can be made. Jordan, in a review on epidemic influenza (23), wrote: Until a coincidence or close sequence of the two diseases has been more convincingly demonstrated, it seems premature to discuss the existence of a neurotropic influenza virus or to speculate on the activation of an encephalitis virus by an influenza virus, or on the nature of the encephalitic component of a complex grippe virus. Although written in 1927, the intriguing questions he raised still cannot be adequately addressed (24, 25).

Clinical symptoms and pathological findings during the 1918 influenza pandemic were predominantly respiratory ones. Necrotic lesions in systemic organs like those seen in virulent avian influenza infections were not observed. From a histopathologic standpoint, this suggests that the 1918 virus, even if pantropic, did not behave like a fowl plague virus does in infected birds.

On the other hand, a subset of 1918 flu victims died quite suddenly with massive pulmonary edema or hemorrhage. These changes were not unique to the 1918 pandemic but have been observed, on a much lesser scale, in the 1957 pandemic and other flu outbreaks. In my view, the histologic changes suggest a direct cytopathic effect, perhaps with damage to vascular endothelium of the respiratory system. Could this be the result of enhanced HA cleavability allowing, if not pantropicity, at least a relaxation of the usual exclusive pneumotropism? Only by sequence analysis of the 1918 virus can we begin to address these questions. Thanks to the model of Goto and Kawaoka (1), another potential explanation of the virulence of the 1918 flu can be explored.

Next Section
<H2>Acknowledgments</H2>I thank Ann H. Reid and Thomas G. Fanning for helpful discussion and comments on the manuscript. This work was supported in part by grants from the American Registry of Pathology and the Department of Veteran?s Affairs and by the intramural funds of the Armed Forces Institute of Pathology.

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

for more on the above topic, see also:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=114497

from the abstract:

Since plasminogen circulates in the bloodstream and is therefore widely distributed throughout the body, we proposed a novel mechanism by which the WSN virus might acquire virulence in mice?i.e., that the acquisition of plasminogen-binding activity by the NA leads to HA cleavage in multiple organs (including the brain), thereby enhancing virulence

 

[mixin]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

I had pneumonia from H2N2 in 1957 & spent a miserable (despite antibiotics) month in bed! Don't discount effects of even a novel antigen influenza.

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I know any pneumonia can be bad; but from what I've read, viral pneumonia usually can be treated with bedrest. Unless a person has other health problems.

Antibiotics aren't prescribed for viral pneumonia because they do nothing for viruses. If they gave you antibiotics, it's likely you had bacterial pneumonia or a mis-diagnosis. (Or since I'm not a Dr., I'm just talking nonsense )

"However, if you see your doctor within 48 hours of the start of your symptoms, you may be given another type of drug called Amantadine (uh-MAN-tuh-deen) which helps treat certain viruses."
Viral Pneumonia: http://www.healthsquare.com/mc/fgmc0407.htm

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

1957 H2N2 cause 70,000 US deaths & over 1,000,000 globally - it wasn't routine.

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[mixin]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Ahhhh, I was missing the point it was the pandemic. And you are correct that it wasn't an ordinary flu. I know next to nothing about that pandemic; I remember hearing about it but haven't read anything at all.

So was yours viral or bacterial?

And I'm glad you're here with us today.

 

[Giuseppe]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Hong Kong leads fight against killer pneumococcal disease [Antara]

Hong Kong leads fight against killer pneumococcal disease

ASAP welcomes the Hong Kong Governments commitment to include the pneumococcal vaccine into the Childhood Immunisation Programme


Hong Kong, (ANTARA News/Medianet International-AsiaNet) --

The Asian Strategic Alliance for Pneumococcal disease prevention (ASAP) is encouraged by the Hong Kong governments recent announcement to include the pneumococcal conjugate vaccine into the Childhood Immunisation Programme.

Professor Lulu Bravo, Chairperson of ASAP said, On behalf of families with young children, the Hong Kong government has taken a significant step forward in helping to protect children from pneumococcal disease through routine vaccination. We eagerly await details of the governments plans to implement the pneumococcal immunisation programme.

The Hong Kong government has indicated that the programme is expected to start by September of 2009.

Each day that countries across Asia Pacific delay the introduction of the pneumococcal vaccine, children are at risk of contracting this potentially debilitating and fatal disease, said Professor Bravo.

The Governments announcement of the inclusion of pneumococcal vaccine in their childhood immunisation programme brings Hong Kong in line with Australia and New Zealand as the leading countries in Asia Pacific to have acted upon the World Health Organisations recommendation to implement a childhood immunisation programme for pneumococcal disease.

Other Asia Pacific countries/regions have evidence to support a national immunisation programme and we hope they will emulate the Hong Kong example to address the significant burden of pneumococcal disease.

Professor Bravo emphasised that by routinely vaccinating our children against pneumococcal disease, we not only protect these children but in addition, have the ability to help protect the broader community unvaccinated children, parents and grandparents through a process of herd protection.

Media enquiries and interview requests: ASAP Secretariat Lisa Sullivan In Vivo Communications (Asia) Pte Ltd 103 Beach Road #06-01/02 Premier Centre Singapore 189704 Email: ASAP@invivocom.com Phone: +65 8233 4542

Background on Pneumococcal Disease (PD)

Pneumococcal disease (which includes meningitis, pneumonia, bacteremia, and acute otitis media) is estimated to result in up to 1 million deaths each year in children, most of whom are in developing countries. In fact, given the significant burden of pneumococcal disease and demonstrated vaccine efficacy, the World Health Organisation (WHO) has recommended the priority inclusion of PCV7 in national childhood immunisation programs worldwide.2;3.

About Asian Strategic Alliance for Pneumococcal Disease Prevention

Asian Strategic Alliance for Pneumococcal disease prevention (ASAP) ASAP was launched on December 14, 2007, and is the first and only group of healthcare professionals in this region formed to specifically focus resources on PD in Asia Pacific. It is the only Asian group to join the growing number of experts from international organizations like the International Vaccine Institute (IVI) in the collective effort to raise awareness of infectious diseases like PD and its prevention.

ASAP is affiliated with the global Pneumococcal Awareness Council of Experts (PACE) and the Asian Society of Paediatric Infectious Diseases (ASPID). It also collaborates with other public health and pediatric groups to achieve its mission of containing and controlling pneumococcal disease in the Asia Pacific region through awareness, surveillance, advocacy and prevention.

[1] World Health Organisation. Pneumococcal vaccines. Wkly Epidemiol Record 2003;14:110119. Available at: http://www.who.int/wer/2003/en/wer7814.pdf. Accessed July 20, 2006.
[2] World Health Organisation. Pneumococcal conjugate vaccine for childhood immunization, March 2007- WHO position paper. Wkly Epidemiol Record 2007;12: 93-104.
[3] World Health Organisation. Meeting of the Immunization Strategic Advisory Group of Experts, November 2006- Conclusions and Recommendations. Wkly Epidemiol Record 2007; 1/2:1-16.

SOURCE: Asian Strategic Alliance for Pneumococcal Disease Prevention
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​

<cite cite="http://www.antara.co.id/en/arc/2008/11/3/hong-kong-leads-fight-against-killer-pneumococcal-disease/">ANTARA :: Hong Kong leads fight against killer pneumococcal disease</cite>

 

[AlaskaDenise]

Re: PCV7 Vaccine Could Prevent 357,000 Deaths in Pandemic

Is this the same vaccine as Prevenar, mentioned in 4-15-2008 here. below is a excerpt:

The vaccine is given at two, four and 13 months and provides protection against seven of the commonest types of pneumonia. It is safe and highly effective ? cases of invasive pneumococcal disease caused by the serotypes covered by the vaccine have fallen by 90 per cent in two years. But there are more than 90 known strains of the bacterium that causes pneumonia. When one is eliminated, it creates an opportunity for another to take its place. In the US, where Prevenar was introduced in 2000, researchers have reported an emergence of "sero-replacement" disease ? types of pneumonia not covered by the vaccine.

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