H5N1 facts, not fear

25 January 2012

Peter Palese and Taia Wang have written a compelling article that uses scientific facts to address the controversy over publication of research involving transmission of avian influenza H5N1 in ferrets. In response to calls in the media to destroy the viruses, curtail the research, and protect the public from frightening research, they write that “fear needs to be put to rest with solid science and not speculation”.

The authors begin with the facts: they indicate that the object of ferret-to-ferret passage of avian H5N1 influenza virus was to determine whether sustainable aerosol transmission could be achieved in this animal model. The finding that transmission in ferrets is conferred by a small number of mutations emphasizes the need for continued surveillance of H5 viruses and development of vaccines and antivirals.

Are these studies relevant to humans?

Ferrets are quite susceptible to infection with influenza viruses. However, it is not clear that all virus strains that replicate in and transmit between ferrets necessarily do so in humans. Ferrets are also more likely than humans to have disseminated, multiorgan influenza disease including neurological sequelae….one cannot directly extrapolate from the data to make predictions about humans.

Under the heading ‘fear’, they address the heart of this controversy, the notion that the fatality rate for human H5 infections is greater than 50%:

…in order for a case to be confirmed by WHO, a person must have an acute, febrile respiratory illness with known H5 exposure in the 7 days preceding and have molecular confirmation of H5 infection by a WHO approved laboratory. This definition does not allow for asymptomatic infections and essentially requires that a person actively seek medical help at a hospital that is equipped to draw samples and ship them to an approved laboratory….it seems unlikely that even a small fraction of the total number of infected cases has been accounted for under the WHO surveillance system.

They also review seroevidence in humans for H5 infections:

Of the 10 largest studies of which we are aware…eight report rates ranging from 0.2% to 5.6%….even if only a low percentage of the rural population is asymptomatically/subclinically infected, the case fatality rate that is offered by the WHO – and that is driving this controversy – is likely orders of magnitude too high.

The authors believe that selection of these papers for redaction by the National Science Advisory Board for Biosecurity appears arbitrary, considering what has been published on influenza in the past:

In 2005, the complete sequences for the 1918 pandemic influenza virus were published…in 2006, both Science and Nature published reports of specific mutations that enable the H5 viral hemagglutinin to bind human, rather than avian tissues. In 2012, a report from the CDC that bears striking resemblance, in principle, to the works by Fouchier and Kawaoka was already published in Virology: it describes mutations in an H5N1 virus that confer airborne transmissibility between ferrets.

Finally the address the question: Could the data from these two papers realistically be used to generate an H5N1 biologic weapon?

The answer is simply no.

Everyone should read this article, including anyone who is concerned about the safety of the H5N1 experiments; biosecurity analysts who do not seem to understand the underlying science; and science writers who propagate misinformation about the virus.

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Lipkin in ContagionHosts: Vincent Racaniello, Dickson DespommierRich Condit, and Alan Dove

The complete TWiVome deconstructs the movie Contagion.

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In letters to Science and Nature, the authors of the controversial avian H5N1 influenza virus transmission experiments in ferrets, together with other influenza virologists, have agreed to a 60 day moratorium on transmission research:

…we have agreed on a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. In addition, no experiments with live H5N1 or H5 HA reassortant viruses already shown to be transmissible in ferrets will be conducted during this time.

They write that research will continue on assessing the “transmissibility of H5N1 influenza viruses that emerge in nature and pose a continuing threat to human health”.

This research is being halted because of the concerns that ferret-transmissible H5N1 viruses may escape from laboratories. They argue that the finding in two laboratories that viruses with a hemagglutinin (HA) protein from highly pathogenic avian H5N1 influenza viruses can become transmissible in ferrets advances our understanding of influenza transmission. Nevertheless,

We recognize that we and the rest of the scientific community need to clearly explain the benefits of this important research and the measures taken to minimize its possible risks. We propose to do so in an international forum in which the scientific community comes together to discuss and debate these issues.

I agree in principle with this decision, because the argument over this research has become increasingly polarized in recent weeks, with a distressing demarcation between those who believe the work should proceed, and those who feel it should not be done. A dialogue to identify the crucial issues and develop plans to address them, while continuing this important line of research, is certainly welcome.

I am curious to see who will participate in the proposed dialogue. I do hope it will be a balanced forum: a fair mix of microbiologists, especially those working on influenza virus, and those interested in biosecurity. As I have said before, scientists will listen to the policy analysts, but the latter must also understand the science.

Update: Alan Dove has written an honest analysis of the moratorium announcement.

Related:

Palese: Don’t censor live-saving science
N.Y. Times: H5N1 ferret research should not have been done
Should we fear avian H5N1 influenza?
A bad day for science
Ferreting out influenza H5N1

5 comments

w3310 virology 2012The third annual installment of my virology course at Columbia University, Biology W3310, has begun. This course, which I taught for the first time in 2009, is intended for advanced undergraduates and will be taught at the Morningside Campus.

Until I started this course, no instruction in virology had been offered at the Morningside Heights campus of Columbia University since the late 1980s. This is a serious omission for a first-class University. Sending graduates into the world without even a fundamental understanding of viruses and viral disease is inexcusable.

Course enrollment has steadily increased: 45 students in the 2009, 66 students in 2010, and an amazing 88 students this year. I am gratified that so many students want to learn about the world of viruses. From the photo you can see that the classroom is full, so if interest in the course continues to increase, we will need a larger room.

Most readers of virology blog will not be able to sit in on each lecture – but you can still watch every one of them. You will find a videocast of each lecture at the course website, at my page on Vimeo, and at iTunes University (link pending). An archive of the 2011 version of this course is available online or at iTunes University. I will announce when each lecture is posted on Twitter and Google+. Virology is a rapidly moving field, so rest assured that this year’s version of the course will be different.

The goal of Virology W3310 is to provide an understanding of how viruses are built, how they replicate and evolve, how they cause disease, and how to prevent infection. After taking the course, some of the students might want to become virologists. The course will also provide the knowledge required to make informed decisions about health issues such as immunization against viral infections.

Thanks to the internet, the information in my virology course is accessible to everyone.

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How lethal is ebolavirus?

18 January 2012

Ebola seropositivity GabonAfter we discussed newly discovered entry factors for ebolavirus and hepatitis C virus on TWiV 166, the New York Times covered part of the story in Key protein may give Ebola virus its opening. Given my recent interest in the case fatality ratio of avian influenza H5N1, I was intrigued by the following introductory statement:

Of the pathogens that keep worried scientists awake at night, few rival Ebola for ruthless efficiency. The virus contains just seven genes, yet it manages to kill up to 90 percent of the people it infects.

Is it true that the fatality rate of ebolavirus is ‘up to 90 percent’? According to the WHO page on Ebola haemorrhagic fever,

Zaïre, Sudan and Bundibugyo species have been associated with large Ebola haemorrhagic fever (EHF) outbreaks in Africa with high case fatality ratio (25–90%) while Côte d’Ivoire and Reston have not. Reston species can infect humans but no serious illness or death in humans have been reported to date.

There have been roughly 1850 recorded cases with over 1200 deaths since ebolavirus was discovered, an average fatality rate of 65%. But have there been only 1850 human infections?

The answer is clearly no. The results of several serological surveys have shown that many individuals have antibodies against Zaire ebolavirus – purportedly the most lethal. The results of one study revealed antibodies in 10% of individuals in non epidemic regions of Africa. A similar seroprevalence rate (9.5%) was reported in villages near Kikwit, DRC where an outbreak occurred in 1995. In addition, a 13.2% seroprevalence was detected in the Aka Pygmy population of Central African Republic. No Ebola hemorrhagic fever cases were reported in these areas.

A more recent study examined sera from 4,349 individuals in 220 villages in Gabon. Antibodies against Zaire ebolavirus were detected in 15.3% of those tested, with the highest levels in forested regions (see map). The authors believe that the seropositive individuals had mild or asymptomatic ebolavirus infection:

The high frequency of ‘immune’ individuals with no disease or outbreak history raises questions as to the real pathogenicity of ZEBOV for humans in ‘natural’ conditions.

These findings indicate that the fatality rates of Zaire ebolavirus that are quoted widely are likely to be vast overestimates. Why the infection is more lethal during outbreak conditions is not known. One possibility is related to the size of the viral inoculum received. During outbreaks the virus is spread by contact with the blood, secretions, organs or other body fluids of infected individuals, which contain very large quantities of virus. In contrast, infections in nature – by contact with contaminated fruit, for example – may involve far less virus.

Whether we are discussing avian H5N1 influenza, ebolavirus, or even the fictitious MEV-1, do not assume that widely quoted fatality rates are correct – check the scientific literature!

Related:

Should we fear avian H5N1 influenza?

Becquart P, Wauquier N, Mahlakõiv T, Nkoghe D, Padilla C, Souris M, Ollomo B, Gonzalez JP, De Lamballerie X, Kazanji M, & Leroy EM (2010). High prevalence of both humoral and cellular immunity to Zaire ebolavirus among rural populations in Gabon. PloS one, 5 (2) PMID: 20161740

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bushmeatThe finding of viral nucleic acid sequences in illegally imported wildlife products has attracted the attention of the New York Times, which published an article entitled From the jungle to J.F.K., viruses cross borders in monkey meat. It begins with a scary scenario:

This may read like a passage from a Richard Preston novel, but all an enterprising virus needs to do is jump aboard a traveling human or animal, and bam — the potential for a catastrophe akin to the 1918 Spanish influenza pandemic could emerge. That’s why the Centers for Disease Control and the Wildlife Conservation Society decided to undertake their first surveillance efforts for diseases of animal origins crossing in the United States.

However, the PLoS One paper that is cited in support of this story found short viral sequences, not viruses, in material confiscated at several airports. The authors of this report extracted nucleic acids from confiscated specimens (which included fresh, raw, lightly smoked or dried samples from chimpanzees, mangabeys, guenons, and rats) and screened them for pathogen nucleic acids by polymerase chain reaction (PCR). The authors note that “RNA quality was low with a predominance of degraded, low molecular weight fragments in the samples”. They identified small PCR DNA products from the genomes of simian foamy virus (a retrovirus) and herpesviruses in 15 out of 48 specimens. No complete viral genomes or infectious viruses are reported in the paper.

Perhaps the Times was mislead by the title of the PLoS One paper: Zoonotic Viruses Associated with Illegally Imported Wildlife Products. The abstract is similarly misleading:

Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples.

The authors correctly report their results at the end of the introduction:

Here we report finding sequences of simian retroviruses and herpesviruses in bushmeat confiscated at five US airports

Infectious viruses might accompany imported smoked monkey heads, dried bats and rat parts. The presence of small fragments of viral nucleic acids suggests that these materials were indeed once infected. But it is a large leap of faith to suggest that infectious agents are still present. It’s a good idea to use PCR to screen such material, but it is important to be specific when reporting the results. My suggestions for revised titles: Zoonotic viral sequences associated with illegally imported wildlife products (PLoS One) and From the jungle to J.F.K., small fragments of viral nucleic acids cross borders in monkey meat (NY Times). Far less interesting, but factually correct.

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npc1 ebolaHosts: Vincent Racaniello, Dickson DespommierRich Condit, and Alan Dove

Vincent, Dickson, Rich, and Alan review cell proteins essential for entry of hepatitis C, Ebola, and measles viruses.

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Year in polio 2011A year has passed since the last reported case of poliomyelitis in India, which occurred on 13 January 2011 in a two year old girl in Howrah, West Bengal. If no additional cases are reported in the next few weeks (some samples are currently being tested for the virus), then it will mark the first time that India has been polio free for one year.

This achievement represents a remarkable turnaround for India, where control of the disease had for years been extremely difficult. As recently as 2009 there were 741 confirmed cases of polio caused by wild-type virus (as opposed to vaccine-derived virus) in India. The tide turned in 2010 with only 42 confirmed polio cases, and in calendar year 2011 there was just one. That is why the 2011 map marking locations of confirmed wild polio cases in India (see figure) shows only one red dot (paralysis caused by type 1 poliovirus) in the country. The blue dots indicate cases caused by type 3 poliovirus.

The challenge now is to keep India free of polio. The map shows why this will be difficult – there are many red dots (cases of type 1 polio) in neighboring Pakistan and Afghanistan. Poliovirus does not respect national borders - China had been free of polio since 1999, but now there are red dots in that country. That outbreak was imported from Pakistan. Even the polio cases in more distant countries such as Africa constitute a threat. As long as there is polio somewhere, all countries must maintain extensive immunization programs. Whether or not that will happen depends upon money, determination, and allowing immunization campaigns to proceed without interruption.

Once polio was eradicated from the United States, the only poliomyelitis was caused by the Sabin vaccine. Consequently this country switched to the use of inactivated vaccine in 2000. As other countries eliminate the disease, vaccine-associated poliomyelitis will become more prominent. If eradication of polio is achieved, the world will have to switch to using inactivated poliovaccine.

Related:

Wild poliovirus in China
Dreaming of inactivated poliovaccine
Poliomyelitis after a twelve year incubation period
Poliovirus vaccine litigation

 

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peter paleseRenowned influenza virologist Peter Palese has penned an opinion column for the science journal Nature in which he uses his experience in reconstructing the 1918 pandemic influenza virus strain to question the censoring of H5N1 results by the National Science Advisory Board for Biosecurity (NSABB):

My colleagues and I were at the centre of a similar controversy in 2005, when we reconstructed the 1918 flu virus, which had killed up to 50 million people worldwide.

As Palese and colleagues readied a manuscript describing these remarkable findings, the NSABB intervened. Palese explained why publishing the work would allow studies on why the virus is dangerous. The NSABB agreed and allowed publication. That was an important stimulus for work on the virus:

After we published our full paper…researchers poured into the field who probably would not otherwise have done, leading to hundreds of papers about the 1918 virus. As a result, we now know that the virus is sensitive to the seasonal flu vaccine, as well as to the common flu drugs amantadine (Symmetrel) and oseltamivir (Tamiflu). Had we not reconstructed the virus and shared our results with the community, we would still be in fear that a nefarious scientist would recreate the Spanish flu and release it on an unprotected world. We now know such a worst-case scenario is no longer possible.

In light of this positive experience, Palese does not understand why the NSABB today does not want to make public the mutations that allow aerial transmission of H5N1 in ferrets. He believes that knowing the mutations will allow a rapid response if they are observed in nature. His conclusion:

The more danger a pathogen poses, the more important it is to study it (under appropriate containment conditions), and to share the results with the scientific community. Slowing down the scientific enterprise will not ‘protect’ the public — it only makes us more vulnerable.

Why is the NSABB taking a different stance on influenza research today compared with 2005? A major factor may be the perception that the fatality rate of H5N1 influenza virus in humans is 60%, compared with 2.5% for the 1918 H1N1 strain – although the latter is not insignificant. As I have pointed out previously, that assumption is incorrect.

Palese hopes that the scientific community will convice the NSABB to change its mind – otherwise who will enter a field in which you cannot publish your most interesting results?

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Science magazine is conducting a live chat about research that produced H5N1 influenza strains that are more easily transmissible between ferrets. Among the topics to be addressed will be the benefits and risks of the H5N1 transmissibility studies and whether they should be published in full; and should experiments that could help aspiring bioterrorists be more tightly regulated.

The guests will be epidemiologist and NSABB member Michael Osterholm, PhD, MPH, Director of the Center for Infectious Disease Research and Policy (CIDRAP), and influenza virologist Andrew Pekosz, PhD, Associate Professor in the Department of Microbiology and Immunology, Johns Hopkins University.

The live chat begins at 3 p.m. EST on Thursday, 12 January. You can join the chat here on virology blog (below) or at the Science website. Questions may be entered in the comment box below before the chat starts.

 

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