New Rules for Expedited Flu Vaccine Licensing

CNN is reporting that on Thursday the FDA will announce new draft rules intended to accelerate the approval of new flu vaccines.  This is excellent news.  According to the story, "Eventually, the guidelines could knock one to two years off the time it takes to develop and license a new flu vaccine."

Here is all the good stuff:

...The guidelines make clear there are a variety of approaches to creating vaccines to fight the next pandemic.

The guidelines allow for emergency approval if a completely new super-strain of flu suddenly appears. Or, manufacturers could systematically create and stockpile a library of vaccines against brewing new strains.

They even allow for the possibility of one day vaccinating people against a potential future pandemic strain at the same time they get their regular winter flu shot.

The last point is interesting, because it is an example of explicitly trying to get out in front of a pandemic strain before it appears.  The biggest reason H5N1 is a threat is that humans have never been exposed to a virus like it.  We are "immune naive", which means we have no preexisting antibodies or lymphocytes primed to respond to this particular virus.

Additional interesting policy tidbits:

In the case of a previously approved flu vaccine, manufacturers could tweak the vaccine for use against a new flu strain without having to seek a new license from the FDA, according to the draft documents.

Additionally, a manufacturer could receive "accelerated approval" for a new flu vaccine by performing studies showing that recipients experienced a surge in protective immune-system cells.

This is all good stuff, and comes not a moment too soon.  Okay, it comes a couple of years late.  We're way behind in preparing technological responses either to large outbreaks of infectious disease or to bioterror attacks.  The draft rules are putatively open for comment for 90 days -- if the rules turn out to be as well constructed as CNN is reporting, then everyone should enthusiastically support these proposed changes.

I'll post more when the official documents are released.

Avian Flu as a Harbinger of Zoonotic Diseases

As most people have heard by now, H5N1 has reached Germany and is confirmed to have killed a cat (AP via the NY Times).  I think the time scale is of interest here.  The virus has only just reached Western Europe, evidently via migrating birds, and already it has jumped to mammals.  In contrast, there appear to have been few cases in felines in Asia, despite the amount of exposure mammals have had there.  From the AP report:

In addition to the large cats infected in Thailand, three house catsnear Bangkok were found to be infected with the virus in February 2004. In that case, officials said one cat ate a dead chicken on a farm where there was a bird flu outbreak, and the virus apparently spread to the others.

I suppose its possible cat deaths are going unreported throughout Asia, but if the AP report is correct then  transmission to cats is very low probability, and I find it odd that the virus is already confirmed to have killed a cat in Germany.  It makes one wonder how the sequence is changing.

Fortunately, there are as of yet no known cases of cat-to-human transmission.  But human exposure to the virus has only just begun in Europe, and the coming months will increase this contact.

All news reports seem to agree that the virus arrived in France and Germany via migrating wild birds.  In an article focusing on the effects of the virus on the French poultry industry, Craig Smith notes in the New York Times that:

...The real threat, many experts fear, may come in the weeks ahead as pintail, garganey and shoveler ducks begin arriving from their wintering grounds in Africa, where the virus has already spread among poultry. The annual migration toward northern breeding grounds is expected to last until the end of May.

Smith also describes how migration patterns have been somewhat unusual this year due to extremely cold weather.  Thus the spread of the virus may be enhanced by changing weather patterns, increasing the likelihood of transportation into areas of the world densely populated by both humans and domesticated animals.  This sort of thing is only going to happen more often.

The AP (via the NY Times) recently picked up this thread with an article entitled, "Scientists See Growing Animal - Disease Risk."  The article begins, "Humans risk being overrun by diseases from the animal world, according to researchers who have documented 38 illnesses that have made that jump over the past 25 years," and winds up:

One explanation may be the recent and wide-scale changes in how people interact with the environment in a more densely populated world that is growing warmer and in which travel is faster and move extensive, Marano said. Those changes can ensure that pathogens no longer stay restricted to animals, she added. Examples from recent human history include HIV, Marburg, SARS and other viruses.

That prospect leaves open the question of what future threats await humans.

''It always surprises us. We think that avian flu will be the next emerging disease. My guess is something else might come out before that,'' said Alan Barrett, of the University of Texas Medical Branch at Galveston. ''It's very hard to anticipate what comes next.''

SARS, in particular, is an excellent example of surprise from nature.  It is also an example of how ill prepared we are for emerging diseases.  It is clear from recent work that if the SARS coronavirus had been just a little more virulent, and if it had spread just a little more before symptoms emerged, then the epidemic would likely not have been held in check by public health measures.  Moreover, it is only because coronaviruses caught the attention of a talented virologist several years before that the community was able to get a handle on the virus as quickly as it did.  More on this in an upcoming post.

(UPDATE, 5 March 06: Ralph Baric is the virologist mentioned above.  Here's the story.)

DNA Vaccine for Ebola

The AP (via the Washington Post) is reporting that the NIH has passed safety trials on a DNA vaccine for the Ebola virus.

From the article:

[Dr. Gary Nabel] and colleagues at the NIH's Vaccine Research Center developed a vaccine made of DNA strands that encode three Ebola proteins. They boosted that vaccine with a weakened cold-related virus, and the combination protected monkeys exposed to Ebola.

The first human testing looked just at the vaccine's DNA portion; the full combination will be tested later.

It will be interesting to see how they go about testing the effectiveness of the vaccine in humans.  There is at present no cure for Ebola, so who is going to volunteer for the test?

The vaccine was reported at a meeting last month.  I'll post additional details as they become available.

H5N1 in France, India.

Reuters (via the NY Times) is reporting that H5N1 has been confirmed in poultry and people in India, and appears to be the cause of death of ducks in France.  Check that -- the radio news just said H5N1 is confirmed in France.  No print/web confirmation yet that I see.

These results may be consistent with the notion of H5N1 being spread both through migratory birds and through domesticated poultry, presumably with poultry being transported across borders, often illegally.  This debate is ongoing at ProMED.  Some quick checking by Todd Harrington at bio-era suggests the flow of poultry from China and Turkey to Nigeria isn't as promiscuous as claimed by the recent Washington Post article, and it seems all legal poultry exports from China are now as cooked meat.  All legal exports, mind you, from a country with absurdly long borders.  All this is just more cause for concern and confusion, it seems.

Alas, even the best informed people are having trouble figuring this out.

Avian Flu in Africa May Have Arrived in Poultry

The Washington Post is reporting that, "The lethal strain of H5N1 bird flu found in Nigeria this month probably got there in poultry and not through the movement of wild birds." 

The article, by David Brown, quotes Billy Karesh of the Wildlife Conservation Society in New York, with whom I collaborate through Bio Economic Research Associates:

I would never rule out wild birds. But I think we have to look at the most probable routes, and the most probable route would be poultry. How did it skip the whole Nile Delta and get to Nigeria? That kind of bothers me. Common sense would dictate that it should be all over Egypt by now.

Though I've been skeptical about transmission via traveling poultry, I can't argue with Dr. Karesh's reasoning.  Mr. Brown also writes that:

The first Nigerian cases were found at a commercial farm with 46,000 chickens, not among backyard flocks that would have greater contact with wild birds. Nigeria imports more than a million chicks a year from countries that include Turkey, where H5N1 appeared last fall, and China, where it has circulated for a decade.

So there is at least trade in poultry from Asia towards Nigeria, and perhaps also from Asia towards Turkey, though I am still checking into the latter possibility.  But even if shipping of poultry turns out to explain the appearance of the virus in Turkey, it seems to be showing up in wild birds first in other countries, for example last week in Italy, Greece, and Bulgaria, and just this week in Germany, Austria, and Iran.

Which leads me to think we will see the virus all over Western Europe in a matter of weeks.  Of course, nobody still has any idea how this is going to turn out in the long run.

Bird Flu in Italy, Greece, and Bulgaria

The New York Times is reporting today that, "Bird Flu Detected in Swans in Italy, Greece and Bulgaria."  It seems that only very preliminary testing has been done so far, but enough to identify H5N1 as the cause of death in at least some wild birds found in the past few days.  The article notes that the virus was roughly identified via rapid screening:

In Italy, police officers near Messina, in Sicily, found two dead swans on Thursday and performed rapid screening tests on them in the wild, which suggested that the swans had a flu virus, according to ANSA, the official Italian news agency.

I find this surprising and impressive.  The cops in Italy are equipped and trained for biosecurity work?  And what tests are they using?  ELISA?  PCR?  Something more like a pregnancy test?  Does anybody reading this know the details?  Were the tests actually performed by beat cops, or were specially trained technicians brought in when the birds were found?  Perhaps this is an indication of how well prepared the Italians are to host the Olympics. 

No sign of the virus in domestic poultry yet.  This would be consistent with the notion that the virus is in fact spread by migrating birds rather than by human travel and trade, a dispute that I addressed when H5N1 showed up in Turkey.

siRNA for Treating the Flu

The study of RNA interference and its therapeutic application are moving so fast I have almost given up trying to keep on top of it.  But we should all pay more attention, because it appears that inhaled siRNA (short interfering RNA) may be an excellent rapid-response technology for disease outbreak situations. 

(Update 7 Feb 06.  Here are a couple of readable primers on siRNA from Answers.com and Wikipedia.)

Previous work has shown inhibition of flu viruses in cell culture and in mice using siRNA.  The experiments in cell culture are nice for demonstrating basic biology, and the work in mice demonstrates physiological effectiveness, but both are a long way from showing anything safely works in humans.   This is particularly true of the work in mice, because compounds are often delivered via a massive injection into a tail vein, which you just can't do in humans.

A paper in the January 2005 edition of Nature Medicine (PubMed) demonstrated inhibition of two negative stranded RNA viruses via nasal administration of siRNA in mice.  Still in mice, but the authors are confident that the results show the technique is amenable to use with nasal inhalers in humans.  Yes, you will probably sneeze immediately, but you will also probably be protected from the flu.

Bitko, et al., start off by noting that:

Viral infection of the respiratory tract is the most common cause of infantile hospitalization in the developed world with an estimated 91,000 annual admissions in the US at a cost of $300 million. [Respiratory syncytial virus (RSV)] and [parainfluenza virus (PIV)] are two major agents of respiratory illness; together, they infect the upper and lower respiratory tracts, leading to croup, pneumonia and bronchiolitis. RSV alone infects essentially all children within the first two years of life and is also a significant cause of morbidity and mortality in the elderly. Infants experiencing RSV bronchiolitis are more likely to develop wheezing and asthma later in life. Research towards effective treatment and a vaccine against RSV has been ongoing for nearly four decades with few successes. Currently, no vaccine is clinically approved for either RSV or PIV. Strains of both viruses also exist for nonhuman animals, causing loss to agriculture and the dairy and meat industries.

In short, respiratory viruses cause considerable disease and death, even in Western countries, and have an economic impact upwards of half a billion dollars per year in the US.  Probably considerably more, if you start adding up productivity losses in the workplace.

After demonstrating previously that siRNA is efficient an antiviral in cell culture, Bitko, et al., set out to test the technology in mice.  Here is where it gets really interesting: They used a free, web based algorithm from the Whitehead Institute to choose the sequences for their RNAs (follow the "about" link to see an explanation of design guidelines).  The rules for designing siRNA are still being worked out, as evidenced by the fact that the best sequence experimentally was, "not suggested by several design engines, including those of Whitehead and Dharmacon, indicating the need for experimental verification of siRNAs."  Not so surprising, given the novelty of the technology.  But I'm fascinated by the fact that anyone could choose a sequence they want to inhibit and have access to design tools.  And the tools will get much better, probably fairly quickly.

Following the design stage, RNA was chemically synthesized, presumably by Dharmacon, who produced RNA for the earlier paper.  Rather than listing absolutely all the details of this work, here are the highlights:

  • The RNA was administered nasally, with and without being complexed with transfection reagent TransIT-TKO.
  • Mice were challenged with virus 4 hours later and then monitored.
  • siRNA reduced viral titer by as much as 99.98%.  The authors estimate that the transfection reagent free siRNA "was 70-80% as effective as siRNA complexed with TransIT-TKO."
  • Mixed siRNA was effective against challenge with multiple viruses.
  • siRNA was effective as a treatment after infection; "[Mice] receiving siRNA at subsequent days (day 2-4) showed gradually less and less protection, although we still observed substantial improvement of weight."

The authors sum up:

The principal finding of this paper is that appropriately designed siRNAs, applied intranasally, offer protection from respiratory infection, as well as providing considerable therapeutic value when administered after infection. We suggest that siRNAs, delivered by small particle aerosols in a simple hand-held inhaler, might prevent or cure pulmonary infections in humans.

I'll continue to post on this topic as I learn more.

Turkey Strain of H5N1 Carries Worrying Mutations

Declan Butler is reporting in tomorrow's Nature that the H5N1 strains currently circulating in Turkey carry mutations, "likely to make the virus better adapted to humans."  According to Dr. Butler:

The Turkey outbreak is unusual, because of the large family clusters ofcases; the fact that many of those infected have only mild symptoms; and the speed with which infections have arisen — twenty cases, including four deaths, in less than two weeks. So scientists are urgently trying to establish whether the virus is behaving differently in this outbreak from previous ones in Asia. In particular, international teams are investigating the possibility that the virus is moving between people.

I speculated briefly last week about the odd behavior of the Turkey strain, and with 20 cases and 4 fatalities in two weeks, there may be reason for concern that the virus has changed its tropism to favor humans.  One of the mutations, in the polymerase gene, is said to be among the ten that caused the 1918 pandemic strain to be so problematic.  The other mutation is in the HA gene, which enables the virus to better target epithelial receptors in the nose and throat.

Dr. Butler reports that together these mutations may make it easier for the virus to be transmitted between humans.  If this were a pandemic strain we would probably know it already.  Unfortunately, human morbidity and mortality are likely the only clues we are going to have; as I've described previously, there is presently no scientific basis to predict the course of the flu.  Alas, human institutions are complicating the process of gathering better data.  Dr. Butler writes that:

Researchers are sequencing more strains from the Turkey cases, to see whether they share the mutations and to check for further changes. Samples were expected to arrive in London on 18 January, after being held up for more than a week in Turkey because of the Eid ul-Adha holiday period.

Given the threat, and the potential for rapid transmission beyond Turkey's borders, why didn't the WHO have a guy (or better yet, a dozen) on the ground chasing samples, with a private jet waiting to fly them to fully outfitted labs in western Europe?  Or perhaps celebration of Eid prevented even the Turks from grasping how the situation was changing?  In any event, I suspect we can ill afford to be without better intelligence from the field.  The AP is just now reporting that Iraq is investigating a potential human death from H5N1, which occurred in a migratory flyway out of Turkey.  One can only hope some of the $1.9B pledged today to fight the bird flu is spent on better surveillance.

Publication of PowderMed's Phase I Influenza DNA Vaccine Trial

This is an important paper.  "Epidermal DNA vaccine for influenza is immunogenic in humans," is "in press" at Vaccine (PubMed), accessible online even though it is undergoing final review.  The manuscript describes initial results from vaccination with a plasmid-based vaccine containing the HA domain of the H3 Panama strain.  I wrote briefly about this last year.

The details:

  • The vaccine appeared well tolerated, with some reaction to the physical effects of the vaccine that amounted to at most a slight rash.  Standard reactions to flu vaccination were observed, including fatigue, fever, headaches.  No antibodies to the double-stranded vaccine itself were detected.
  • The antibody titers are as reported previously, and this paper claims, "The present study is the first successful demonstration of immunogenicity of an influenza DNA vaccine in humans."
  • Increasing doses of the vaccine (up to 4 micrograms) induced increasing antibody titers, with only the largest dose meeting the 21 license requirement of the Committee for Proprietary Medical Products in the European Union.  I would observe that this is still a factor of 250 lower than any intramuscular DNA vaccine up to this point, and well within doses reasonable for widespread manufacturing and inoculation.  The specific antibody kinetics of vaccination with DNA are still unclear, and the authors note that, "The immune response to the DNA vaccine in humans may be qualitatively different than the response to protein vaccines."  Something that requires further study, to be sure.

In addition to the speed, manufacturing, and distribution advantages of DNA vaccines over egg- or cell culture-based approaches, it should be possible to achieve vaccination against multiple strains with one shot.  This could be accomplished either by including plasmids coding for multiple antigenic domains or by tailoring sequences to achieve cross-protection from the same antigen.  That is, it appears careful choice of the antigenic domain can result in the production of antibodies that neutralize more than one strain of a pathogen.

Given that 1) we very likely cannot know ahead of time the sequence of the virus that results in a pandemic, 2) flu viruses have been demonstrated to escape vaccines within 12 months, and 3) traditional vaccines aren't up to the job anyway, DNA vaccines may provide a way to inoculate people against more than one strain.  Because we are slowly developing the capability to monitor the virus in bird populations as well as humans (an endeavor that should have been given a much higher priority in the recent supplemental budget request),  it may soon be possible to include a distribution of antigenic sequences in any given round of inoculations.  This is speculative, to be sure, because there are currently no demonstrated ways of estimating which sequences are likely to be produced by mutation or recombination, but in principle we could produce vaccines effective against a whole range of pathogens, even those that have yet to appear in nature.

However, it is clear we have a lot to learn before this is possible.  A recent review paper in the Japanese Journal of Infectious Disease explores, "Mechanisms of Broad Cross-Protection Provided by Influenza Virus Infection and Their Application to Vaccines."

Hmmm...I was about to write a short summary of this paper, but I'm realizing it will take a bit me longer to digest the contents and do the subject justice.  So, I'll post again on cross-protection and the flu when I have a better grasp of it.