Revisiting The H5N1 CFR Debate

 

 

Source – WHO as of 6/7/12

 

 

 

# 6401

 

One of the more contentious aspects of the H5N1 research debate of the past 8 months has been the argument over the `real’ CFR (Case Fatality Ratio) of the H5N1 virus in humans.

 

The `official’ number – a fatality rate of roughly 60% – is derived from the total known human infections by the virus (606 as of June 7th, 2012), and the total number of fatalities within that group (357)

 

Critics point out that only the sickest of the sick would end up in a testing environment, and that many mild cases would recover and never be counted.

 

The numbers, they maintain, are badly skewed.

 

Last February (see Science: Peter Palese On The CFR of H5N1) the journal Science published a meta-analysis by  Taia T. Wang,  Michael K. Parides &  Peter Palese, that argued that we are likely missing a great many H5N1 infections (perhaps millions), and that the virus is far less lethal than has been assumed in the past.

 

That argument was countered by CIDRAP director Michael T. Osterholm and Nick Kelley in an mBio  article, where they found little serological evidence to suggest that we are missing `millions’ of uncounted H5N1 infections (see mBio: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective).

 

Today, we’ve a new response to the Palese meta-analysis appearing in the journal Science. One with a remarkable pedigree; attached you’ll find some of the biggest names in influenza research:

 

 

Comment on “Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis”

Science 22 June 2012:
Vol. 336 no. 6088 p. 1506
DOI: 10.1126/science.1221434

Maria D. Van Kerkhove, Steven Riley,Marc Lipsitch, Yi Guan, Arnold S. Monto, Robert G. Webster, Maria Zambon, Angus Nicoll, J. S. Malik Peiris, Neil M. Ferguson

Abstract

A better understanding of the severity of H5N1 in humans is needed. Wang et al. (Brevia, 23 March 2012, p. 1463; published online 23 February 2012) over interpret the results of seroprevalence studies and take too little account of underlying uncertainties. Although the true risk of death from H5N1 infection will likely be lower than the 60% of reported laboratory-confirmed cases, there is little evidence of millions of missed infections.

 

Their entire rationale may be read here, and it strongly counters the assessment presented by Wang et al. in the original paper.

 

Dueling opinion pieces, regardless of the credentials of those involved, can’t really settle this argument. What we need are more, and better, seroprevalence studies in places where the H5N1 virus is endemic to come to any firm conclusions.

 

While most researchers accept that the 60% CFR number is probably far too high, as the authors of today’s article caution, in the absence of compelling data to the contrary:

 

“The precautionary principle dictates that we continue to assume that natural H5N1 infection in humans carries a high risk of death”

 

A policy I would certainly endorse.

EID Journal: Guinea Pigs As Reservoirs For Influenza

 

 

# 6369

 

 

From the CDC’s EID Journal we’ve a new study that looks at influenza infections in farm-raised guinea pigs in Ecuador, that provides several surprising results.

 

Ferrets and mice are often used in influenza research, but neither is truly ideal.

 

So in recent years a number of researchers have looked at guinea pigs as possible model mammalian host for influenza virus studies (see PNAS The guinea pig as a transmission model for human influenza viruses by Peter Palese et al. 2006).

 

The success in using guinea pigs in lab studies has led some scientists to wonder just how guinea pigs might fit into the hosting and spread of flu viruses outside of the laboratory.

 

Which brings us to a dispatch (again from Peter Palese et al.) that was published yesterday in the EID journal called:

 

Dispatch

Influenza Virus Infection in Guinea Pigs Raised as Livestock, Ecuador

Victor H. Leyva-Grado, Samira Mubareka, Florian Krammer, Washington B. Cárdenas, and Peter Palese

Abstract

To determine whether guinea pigs are infected with influenza virus in nature, we conducted a serologic study in domestic guinea pigs in Ecuador. Detection of antibodies against influenza A and B raises the question about the role of guinea pigs in the ecology and epidemiology of influenza virus in the region.

 

 

Guinea pigs are raised and used as food in parts of South America (Peruvians reportedly consume more than 65 million of them each year, and they may also be found on the menu in Bolivia, Ecuador, and Columbia).

 

While the consumption of guinea pigs may seem an unusual culinary choice to many of us, it is so entrenched in the Andean culture that in 1753 - when Marcos Zapata painted his version of `The Last Supper’ for Peru (which now hangs in The Cathedral Of Cusco ) - he depicted Christ and the Apostles dining on a platter of cuy, or guinea pig.

Photo Source – Wikipedia.

 

But I digress . . .

 

Most of these animals are raised on small farms, and often in close contact with other livestock as well as humans.

 

Given these conditions, and their propensity for hosting and spreading influenza in laboratory studies, a seroprevalence study was undertaken to see how widespread influenza infection among guinea pigs might be outside of the laboratory.

 

This study examined blood samples from 40 guinea pigs taken from 3 locations across Ecuador, and subsequently found evidence of previous Influenza A infections in a unusually large number of them.

 

The surprises (of which there were several) included:

 

• The high percentage of positive influenza A samples (50% H1, 45% H3)
• The detection of several (n=14)animals carrying antibodies to an H5 virus
• And perhaps the biggest surprise of all – finding evidence of influenza B infections (previously only thought to infect humans) in 27 of the 40 samples tested.

 

 

An earlier seroprevalence study of influenza A among humans in Ecuador showed a seroprevalence of H1 (5.1%) and H3 (5.5%) -  about 1/10th that found in these guinea pigs.

 

The authors suggest that the way these animals are raised (caged together and in close quarters) may facilitate the spread of influenza. 

 

The discovery of H5 antibodies is intriguing, but since this study only tested only for seroreactivity to parts of the H5 virus, further study will be required to identify and quantify the prevalence of avian influenza viruses in this population.

 

And the last finding - that of Influenza B in roughly 2/3rds of the samples – support the idea that this type of influenza can be readily transmitted from humans to other hosts.

 

The authors write:

 

Further studies are needed to isolate and characterize the type B influenza virus present in the population of guinea pigs to determine if there has been an adaptation to the new host or if the guinea pig is only a transient reservoir for the human virus.

 

The authors conclude this dispatch by stating:

 

We did not determine whether guinea pigs are an incidental host for influenza virus infection or, if instead, the virus has been adapted to these animals or if guinea pigs are a natural reservoir for some influenza viruses. To this end, virus isolation and characterization would be necessary to determine the virus strains circulating in this population. In the laboratory, guinea pigs are infected and efficiently transmit influenza viruses to naive hosts without showing any overt clinical signs of disease (1). Therefore, further studies are needed to address the specific role of guinea pigs raised as livestock in the ecology and epidemiology of influenza viruses in the region.

 

 

For more details on the methods used, the full text is available online at this link.

 

While this research might seem a bit obscure to all but the most ardent infectious disease geeks, it serves to show just how little we still know about influenza viruses and their host range,  and that there are still plenty of surprises waiting out there yet to be uncovered.

Science: Peter Palese On The CFR of H5N1

 

 

# 6169

 

 

One of the livelier `sideshows’ in the vigorous debate over the safety and wisdom of H5N1 lab research has been the argument over just how deadly the H5N1 virus really is.

 

Although the virus first appeared 15 years ago in Hong Kong that question remains difficult (perhaps, impossible) to answer.

 

The media has reported, ad nauseum, that the virus kills 6 out of 10 people it infects. Which would give it a CFR (Case Fatality Ratio) about 60%.

 

But then it gets complicated.

 

We literally have no good read on how many people the virus has actually infected.  If `mild’ or asymptomatic infections occur, then they are unlikely to be noticed.

 

A large part of the reason is that surveillance is less than robust in many of the regions where the virus is endemic. Testing – when it is done (and often it isn’t) – has long suffered from sensitivity problems. 

 

Beyond that, many people who get sick (and even die) in places like Cambodia, Vietnam, or China may do so without ever seeking medical care.

 

Intuitively we can say that these cases almost certainly exist, but we have no way to accurately measure them. In truth, even the CDC can’t tell you exactly how many people are sickened or die from the flu (or any other cause) each year.

 

Most scientists would grant that what we see with the H5N1 virus is probably the tip of the iceberg. It is the size of what lies beneath that visible tip that is heavily disputed.

 

Today we’ve a paper, authored by Professor Peter Palese  et. al., that argues that we are likely missing a great many uncounted H5N1 infections, and that the virus is far less lethal than has been assumed in the past.

 

This is similar to the argument that Vincent Racaniello  used last month in his blog Should we fear avian H5N1 influenza?

 

The reason behind this debate – beyond the obvious need to quantify an important aspect of this virus – is the debate over whether this virus is too dangerous to work with in a BSL-3 laboratory environment. 

 

Relegating it to the highest containment labs (BSL-4), it has been argued, would severely restrict the number of scientists (and countries) who could work on this pathogen

 

 

One way to get an idea of the uncounted number of people infected by a virus in a population is to conduct regional seroprevalence studies.

 

You essentially check antibody levels against a specific virus in a representative group of the population.

 

Unfortunately, you don’t end up with a clear cut Infected/Not Infected reading from these tests. You get an antibody titer level, and that requires a subjective decision as to what level constitutes proof of a `previous infection’.

 

Set the bar too high, and you rule out possible cases whose antibodies have declined over time (or who were exposed to an antigenically different H5N1 strain).

 

Make it too low, and you may count people who were exposed to a non-H5 virus or who received such a low viral load as to not develop illness or immunity. 

 

Over the years we’ve seen a number of seroprevalence studies on the H5N1 virus, and the results (and methods) have varied considerably.

 

Palese’s paper appears today in the journal Science (the embargo lifts at 2pm EST), and here he makes his case:

 

Seroevidence for H5N1 Influenza Infections in Humans: Meta-analysis

Taia T. Wang,  Michael K. Parides,  Peter Palese

ABSTRACT

The prevalence of avian H5N1 influenza A infections in humans has not been definitively determined. Cases of H5N1 infection in humans confirmed by the World Health Organization (WHO) are fewer than 600 in number with an overall case fatality rate of >50%.

We hypothesize that the stringent criteria for confirmation of a human case of H5N1 by WHO does not account for a majority of infections, but rather, the select few hospitalized cases that are more likely to be severe and result in poor clinical outcome.

Meta-analysis shows that 1-2% of more than 12,500 study participants from 20 studies had seroevidence for prior H5N1 infection.

 

While stating that we don’t have definitive numbers, Palese writes that if one assumes a 1-2% infection rate among exposed populations, there would likely be millions of people who have been infected by the H5N1 virus.

 

Palese grants that deaths from the virus may also be undercounted, and calls for better studies (something that I think everyone, regardless of where they stand on this issue, would agree with).

 

If we assume that Professor Palese is correct in his assumptions, then the H5N1 would seem to be not much more dangerous than some strains of seasonal flu.

 

A comforting thought.

 

But one that seems at odds with the argument proffered by many scientists calling for aggressive research into the H5N1 virus because of its serious `pandemic potential’.

 

Of course not everyone views the available data in quite the same way as does Professor Palese.

 

We’ll be getting a counter-argument either later today or tomorrow from Michael Osterholm and Nick Kelley of CIDRAP, who have their own analysis coming out in mBio this week (see press release).

 

Stay tuned.

Towards A Universal Flu Vaccine

 

 

 

# 4991

 

 

It’s the Holy Grail of flu researchers; a universal flu shot that could protect against a wide range of flu viruses, and give protection that would last for years.

 

And based on research published yesterday in PNAS, researchers are inching slowly closer to that goal. 

 

The study is dauntingly titled:

 

Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes

1. Taia T. Wang, Gene S. Tan, Rong Hai, Natalie Pica, Lily Ngai,Damian C. Ekiert, Ian A. Wilson,Adolfo García-Sastre, Thomas M. Moran, and Peter Palese

 

And the Abstract – which describes the testing of a synthetic peptide that binds to the stalk of a cross-variety of influenza hemagglutinins in mice – is probably for nonscientists –  a bit of tough sledding.

 

Luckily, we’ve a pair of articles available online that shed a good deal more light on the subject, and in language that is easier to understand.

 

First, from Scientific American, we’ve an interview with co-author Peter Palese –  a familiar name in influenza research - and Professor of microbiology and head of the Department of Microbiology at the Mount Sinai School of Medicine in New York.

 

How Close Is a Universal Influenza Vaccine That Could Provide Lifelong Immunity with One Shot?

The rapidly mutating strains of flu virus have so far thwarted efforts to develop a vaccine that could knock out all varieties with a single injection, but recent advances suggest a synthetic solution. The head of Mount Sinai School of Medicine's microbiology department explains

 

Second, an article by Lauren Gravitz at MIT’s Technology Review, with comments by such notables as Robert Webster, Gary Nabel at NIH, and Terrance Tumpey at the CDC  titled:

 

A Long-lasting Universal Flu Vaccine

Advance could eliminate the need for shots each year for evolving strains.

By Lauren Gravitz

 

Both are good reads.

 

The short version, however, is that researchers have created a synthetic peptide which binds to a slow-to-mutate portion of the viral hemagglutinin that is common across many strains of influenza.

 

This experimental vaccine produced (in mice, at least) varying immune responses against the H1N1, H5N1, and H3N2 viruses . . . with protection that ranged from mild to robust.

 

 

But as the saying goes, if you are sick . . . and you are a mouse . . . there’s a lot that modern science can do for you.

 

What works in mice, however, doesn’t always translate into a viable treatment for humans.  

 

The levels of protection achieved from this vaccine apparently weren’t potent enough  across all subtypes to serve as a stand-alone universal vaccine, but this work is still in its early stages.

 

And even if this technique eventually proves efficacious in humans, it is a long road from testing it on lab mice to having a human-approved drug.

 

But this is real progress, offers a tantalizing avenue for further research,  and gives hope to the idea that someday a universal vaccine might become a reality.