H5N1 in the US

From NBC News, January 22, 2015:

A green-winged teal shot by a hunter in northern Washington state has tested positive for H5N1 bird flu — a relative of the virus that’s infected nearly 700 people globally and killed 400 of them.

[snip]

To make matters more complicated, this strain of H5N1 found in the teal appears to be a mix of H5N1 and the H5N8 found in Washington state and elsewhere in the U.S. as well as in Europe, South Korea, Japan and Taiwan.

The pandemic potential of this version of H5N1 is unknown.

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Cryptic infection of Canadian visitor with H5N1 in China

A resident of Alberta Canada has just died after being infected with H5N1 after visiting Beijing China [hat-tip, NawtyBits].

Some facts:

Date of symptom onset: December 27, 2014
Date of hospitalisation: January 1, 2014
Date of death – January 3, 2014

The person who died first reported symptoms while on Air Canada flight 030 from Beijing to Vancouver on December 27, 2013.

This person presented with unusual neurological symptoms rather than the typical respiratory signs.

There have been no reports of H5N1 in Beijing nor any explanation of how the visitor from Canada was infected.

The odds that one visitor from another country was infected as a result of environmental exposure in China but that no one in China has been infected by the same source are vanishingly low.

As Dr. Niman has pointed out, it is odd that H5N1 cases are being missed in China given the intense scrutiny influenza patients are receiving due to the ongoing reports of H7N9 infections.

As Pixie has pointed out, there is a curious lack of urgency or concern on the part of Chinese officials to uncover how this visitor from Canada was infected, presumably in Beijing. In fact, in this Xinhua story, there is no indication that Chinese officials are attempting to find the source of the infection. This is odd.

So, how did the visitor from Canada get infected with H5N1 in China? At this point, all we can say is that the source is hidden.

Virus Storm

The number of lethal new viruses now assaulting the human species is striking:

MERS/SARS2
H5N1
H7N9
H10N8
pH1N1

Since all of these viruses can kill otherwise healthy young adults, when a new outbreak of an infectious agent occurs, it can be difficult to know which of the many, and growing number, of viruses is responsible. Testing should now involve rapid sequencing of samples. This should not be left to local public health departments. There should be a national system for sample preparation and sequencing with clear protocols for hospital and private practitioners to follow and designated laboratories for the samples to be sent to. The goal should be identification of the virus within 24 hours of a death or a cluster of people with severe illness. If the CDC is unwilling or unable to meet these metrics, States should set up their own protocols and networks. Many States have sufficient expertise and equipment to get this done.

There should be no “mystery” viruses in the 21st Century.

Airborne transmission of H5N1 in ferrets – the Fouchier study

Two studies have recently been published demonstrating that H5N1 can be transmitted in the air in ferrets, one by Dr. Kawaoka’s group, the other by Dr. Fouchier’s group. I have previously discussed the Kawaoka paper. Here, I present some of the findings from the Fouchier paper.

Using their knowledge of influenza biology, these investigators modified the A/Indonesia/5/2005 strain of H5N1 to create three mutations which they believed would increase the odds of airborne spread of the virus – E627K in PB2 and Q222L and G224S in HA. They found that these three mutations were insufficient for this purpose. To create a selective pressure for ferret to ferret spread of the virus, the wild type and the genetically modified versions of H5N1 were used to infect two separate groups of ferrets and then passaged from ferret to ferret by collecting the sneezes of the infected ferrets and using these sneezes to infect additional ferrets. After 10 such passages from ferret to ferret, the genetically modifed, but not the wild type strain of H5N1, was able to infect ferrets through the air. Two additional mutations appeared to be under selection during the passaging process – T156A and H103Y in HA.

One of the ferrets died during the study, but apparently not due to infection through the air. Because the airborne strain had only been passaged 10 times, we do not know what would have happened after many more passages in mammals, as would occur in a pandemic. It is not unreasonable to suppose that the virus would have continued to adapt to mammals under these conditions. And we know that H5N1 which is fully adapted to birds is 100% lethal in some species.

How do the investigators who conducted these studies now view the odds that we will experience a H5N1 pandemic? From the paper:

Given the large numbers of HPAI A/H5N1 virus-infected hosts globally, the high viral mutation rate, and the apparent lack of detrimental effects on fitness of the mutations that confer airborne transmission, it may simply be a matter of chance and time before a human-to-human transmissible A/H5N1 virus emerges.

Airborne transmission of influenza A/H5N1 between ferrets. 2012. Herfst et al. Science. 336: 1534 – 1541.

The Kawaoka droplet transmission H5N1/pH1N1 study

Nature has just published the long-awaited paper by Kawaoka and colleagues describing the creation of a hybrid H5N1/pH1N1 virus which can be transmitted by respiratory droplets between ferrets:

Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets, Nature, May 2, 2012

There are many interesting facets to this study, but this blog will focus on a few key issues of interest to the flu preparedness community.

1. This was a hybrid virus. Only one of the eight genomic segments, haemagglutinin (HA), was derived from H5N1. The other 7 came from the pandemic H1N1 virus (pH1N1).

2. Four mutations in the H5N1 HA genomic segment were sufficient to allow the hybrid virus to spread from ferret to ferret.

3. None of the ferrets died during the course of the experiments. However, one virus was recovered from the brain of one of the ferrets. Since only a small number of ferrets were used, little can be concluded about the potential case fatality rate (CFR) of this virus if it were to occur in the human population except that it would not be rapidly lethal in 100% of the affected individuals. A much larger number of individuals would need to be tested to detect a fatality rate of 2%, the CFR of the 1918 flu virus.

4. A hybrid virus with its HA from H5N1 but the other genomic segments from pH1N1 would not necessarily be expected to be any more lethal than pH1N1. This is because HA is primarily involved in transmission of flu viruses. Although it plays a role in virulence, other genomic segments, for example, PB1, PB2, NA and NS, have been strongly implicated in the pathogenicity of flu viruses. Since these genomic segments were derived from pH1N1, it would not be surprising if the hybrid virus was about as lethal as pH1N1.

5. H5N1 and pH1N1 are genetically compatible. One type of hybrid was produced in these experiments, but others are possible. A hybrid which contained the PB1 or NS from H5N1 with other genomic segments from pH1N1 might have a very different CFR than the virus described in the current work.

6. The mutations which can cause H5N1 HA to permit mammal to mammal transmission are limited. The authors describe a range of mutations in H5N1 HA which did *not* result in increased transmissibility of the virus. Thus, we now know better which variants of H5N1 in the wild are likely to be most dangerous. This also sets the stage for the possibility of developing pre-emptive pandemic vaccines.

Publication of this work is long overdue. The fear that terrorists living in caves could use this information to produce a weapon seems quite ridiculous when reading this paper. The techniques and sophisticated analyses involved in this work are way beyond the limited intellects, knowledge base, and resources available to these groups. Nation-states run by dictators could develop biological weapons using the approaches described here. But if this was their intent, they likely have already pursued experiments to accomplish this without the many constraints researchers in free countries are subject to.

We now know that H5N1 could become easily transmittable between mammals. That knowledge alone will make us safer.

US government endorses publication of H5N1 ferret papers

Not much to say about this other than that it is very good news.

From Science, April 20, 2012

The United States government has formally accepted a recommendation from a biosecurity advisory board to publish two controversial studies of the H5N1 avian influenza virus, moving the pair of papers another step closer to publication.

The announcement came today in a statement from Francis S. Collins, director of the National Institutes of Health, which was posted on NIH’s Web site. It says that Collins and Kathleen Sebelius, the secretary of the Department of Health and Human Services, “concur with the NSABB’s [U.S. National Science Advisory Board for Biosecurity’s] recommendation that the information in the two manuscripts should be communicated fully and we have conveyed our concurrence to the journals considering publication of the manuscripts. This information has clear value to national and international public health preparedness efforts and must be shared with those who are poised to realize the benefits of this research. … The Secretary’s decision takes account of relevant U.S. law, international obligations, and a rigorous analysis of the benefits and risks of publication.”

False Security

From NPR, March 30, 2012

The Obama administration has announced a new policy to handle the risks posed by legitimate biological research that could, in the wrong hands, threaten the public.

The move comes in response to a huge debate over recent experiments on bird flu virus that got funding from the National Institutes of Health. Critics say the work created mutant viruses that could potentially be dangerous for people, or give terrorists a road map for making a bioweapon.

A committee that advises the government called the National Science Advisory Board for Biosecurity (NSABB) is again meeting Friday to discuss those flu studies. Late last year, it recommended keeping some details secret. But a panel of experts, including flu virologists assembled by the World Health Organization, called for full publication.

The new policy is aimed at preventing this kind of controversy from happening in the future. It covers federally-funded research — both ongoing work and future proposals. And it calls for special reviews of work that involves a list of 15 particularly nasty pathogens and toxins, including highly pathogenic bird flu virus, anthrax, and Ebola.

Funding agencies will have to evaluate certain kinds of experiments to see if they pose special risks. The idea is “to really upfront ask the questions: Should they be done? And if so, under what conditions should they be done,” explains Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the NIH.

If an agency wants to fund an experiment that might yield potentially dangerous information, Fauci says, scientists could be asked to hold back on publishing details in order to receive funding.

Or, in some cases, the work might need to be classified. Fauci notes that the NIH does not do classified studies. “We would have to refer it to an agency that does classified research because we don’t,” he says.

This sets a very dangerous precedent. There are lots of types of biological research “that could, in the wrong hands, threaten the public”. Although the intent now may be to restrict this measure to certain types of research, once the precedent is set, there is no guarantee that it will not be extended to others. Who will decide what knowledge could or could not “threaten the public”? If it is politicians (or scientists who depend on the patronage of politicians), then almost by definition, this measure will be politicised. One can get whatever type of research one wants banned by picking the right members of the committee that will do the banning. There are recent of examples of this, for those whose memories go back a few years.

It is also disturbing that there is still no discussion of State sponsored bioweapons research, especially in China. There are many countries with the capacity to do this research without any help from the US. If this research in the US is classified, the general public in the US will have no idea what is or is not possible, what is or is not a threat.

I have a great deal of respect for the US military’s ability to fight conventional wars. However, in my opinion, their work on biological weapons defense is extremely poor. The DoD has demonstrated no grasp of the strategic threat involved nor any particular expertise in developing countermeasures. To be fair, their ability to detect emerging pandemic flu threats is apparently better than the CDC’s as they were the ones who first reported pH1N1. But this is not nearly enough.

The CDC conducted the same types of experiments as Fouchier and Kawaoka but failed to reveal the threat of a high CFR H5N1 pandemic. It would be a mistake to rely on the CDC for this research.

The DoD has USAMRIID, but it is not clear that they have the breadth or depth of personnel to cover all potential agents. Further, scientists there will be hampered if they cannot discuss their work with their colleagues at other institutions (as would happen if the work is classified). Given that the anthrax attacks apparently originated from a scientist at USAMRIID, it is not obvious why entrusting this group with work on dangerous pathogens is safer than to let this work be done by NIH scientists.

In my opinion, this ruling is tantamount to hearing the noise of breaking glass in your house and then pulling the covers over your head. Hiding from the threat will not save you. As scary as it is, your best option is to develop a strategy to defeat it, which may involve confronting the threat head on.

We could have delayed the threat of biological weapons by controlling the sale of gene synthesis machines to foreign countries. But no-one in the US government, including apparently the entire leadership at DoD, seems to have understood the risk of proliferating this technology. Given that the ability to create a high CFR pandemic virus already exists and has been actively pursued by countries like China, the question now is: what is likely to provide our best defense? Part of the answer will involve politically unpalatable decentralisation and the incorporation of citizen resilience in national defense policy. But part of the answer will come from a free exchange of information among the best scientists. We cannot develop countermeasures to a threat if we do not know what it is.