2010 June 15 Tuesday
H1N1 Flu Vaccine Protects Against 1918 Strain

The current H1N1 vaccine provides some protection against the 1918 strain that killed tens of millions of people.

WHAT: Mice injected with a 2009 H1N1 pandemic influenza vaccine and then exposed to high levels of the virus responsible for the 1918 influenza pandemic do not get sick or die, report scientists funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The new vaccine works against the old virus because the 1918 and the 2009 strains of H1N1 influenza share features that allow vaccine-generated antibodies to recognize both viruses. To learn more, similar challenge studies need to be conducted in other animals, including monkeys, but the investigators say their results suggest people who are vaccinated against 2009 H1N1 influenza or were exposed to the virus could have similarly cross-protective antibodies against the 1918 strain of H1N1. This finding, they add, should help allay concerns about the potential consequences of an accidental release of the 1918 influenza virus from high-containment laboratories or its possible use as a bioterror weapon.

The recurrence of a strain like the 1918 influenza pandemic strain would kill tens of millions of people. Since it is possible for such a strain to emerge the ability to provide even partial immunity to a strain similar to the 1918 flu might just save your life.

Some lab mice are now fully prepared for a replay of the 1918 pandemic. I'm picturing these mice venturing out of a research lab into a post-apocalyptic landscape after most humans are dead from a killer flu. The mice head for the local cheese shop confident no humans will block their journey.

The researchers administered to three groups of mice either the 2009 H1N1 influenza vaccine, the seasonal influenza vaccine, or no vaccine at all. Twenty-one days later, the mice were exposed to a lethal dose of the 1918 Spanish influenza virus. The mice receiving the H1N1 vaccine were the only ones to survive, while also exhibiting limited morbidity following the vaccination.

By Randall Parker    2010 June 15 11:20 PM   Entry Permalink | Comments (8)
2009 November 04 Wednesday
Policy Decisions Slow H1N1 Vaccine Production

Why is H1N1 influenza vaccine coming out so slowly in the United States? Dr. Scott Gottlieb, a former FDA deputy commissioner, says a few policy decisions slow the production of vaccine.

Why do adjuvants matter? An adjuvanted H1N1 vaccine being used in Europe contains 3.75 micrograms of vaccine stock. The same vaccine in the U.S., without the adjuvant, requires 15 micrograms of vaccine for equal potency. If we used adjuvants, we could have had four times the number of shots with the same raw material.

Our regulators are more risk-averse. If a much more lethal pandemic flu strain popped up would the regulators continue to be so conservative?

We need to move beyond the use of chicken eggs to produce virus proteins for vaccine. The much more rapid and scalable approach using mammalian cells is already in use in Europe, not so in the US. Again, regulatory conservatism makes a difference.

The third policy decision was to stick for too long with a proven, but slow process for making flu shots that uses chicken eggs to grow the raw vaccine material. Shots can be made much faster using mammalian cells to grow vaccine, and this process is already being used in Europe. The cell-based vaccines are unlikely to be approved in the U.S. Our precaution when it comes to vaccines means we don't easily embrace novel technologies, even if the Europeans would part with some of their limited supply.

Luckily H1N1 isn't lethal to all that many people. Tens of thousands might die. But a repeat of 1918 levels of lethality would require a far far less conservative approach to vaccine approvals. Would the US government make the needed changes in regulatory policy when tens of millions of lives are at stake?

Forget global free trade when lives are at stake. Where the vaccine manufacturing plants are located also matters.

In 2004, only two companies were licensed to sell flu vaccine in the United States; now there are five, but only one, Sanofi-Pasteur, has a domestic plant. The others — GlaxoSmithKline, Novartis, CSL Ltd. and Medimmune — use plants in England, Germany and Australia.

The drawback of relying on foreign plants was made clear recently when the Australian government pressured CSL to keep its vaccine at home instead of fulfilling its contract for 36 million doses of swine flu vaccine for the United States.

H1N1 vaccine production is late.

Frieden said the CDC had a cumulative 26.6 million doses of vaccine available -- far short of the 40 to 80 million that had been forecast for the end of October.

My advice: take vitamin D and clean your hands more often.

By Randall Parker    2009 November 04 11:07 PM   Entry Permalink | Comments (6)
2009 April 28 Tuesday
6 Month Delay Seen For Pandemic Vaccines

We need faster methods for development and production of vaccines for when pandemics happen. A paper in PNAS draws attention to the time lag from emergence of a new influenza strain to availability of vaccines.

New research published today (Monday April 27) from the University of Leicester and University Hospitals of Leicester NHS Trust warns of a six-month time lag before effective vaccines can be manufactured in the event of a pandemic flu outbreak.

By that time, the first wave of pandemic flu may be over before people are vaccinated, says Dr Iain Stephenson, Consultant in Infectious Diseases at the Leicester Royal Infirmary and a Clinical Senior Lecturer at the University of Leicester.

In his paper published in PNAS- Proceedings of the National Academy of Sciences of the USA- Dr Stephenson makes the first case for a pre-pandemic vaccine to mitigate the worst effects of pandemic flu.

He said: "This study is the first to show an effective pre-pandemic vaccine approach. This means that we could vaccinate people potentially many years before a pandemic, to generate memory cells that are long lasting and can be rapidly boosted by a single dose of vaccine when needed."

The paper focuses on the H5N1 avian influenza threat that scientists have been worrying about for years. The swine flu threat probably popped up after the paper was submitted for publication.

A New York Times article also takes a look at vaccine production delays. One problem: right now the flu vaccine industry is gearing up to make their normal yearly vaccine. If they do not start making swine flu vaccine until after the regular vaccine production is done then we'll be more months away from getting swine flu vaccine.

If production of the swine flu vaccine were to start right after that, the first 50 million to 80 million doses would be available by September, Dr. Robinson said.

A full 600 million doses, enough to provide the required two shots for each American, could be finished by January. If immune stimulants called adjuvants were added to the vaccine, that could reduce the dosage needed by each person, allowing enough doses to be ready by late November, he said.

Those doses are only for the US and United States is less than 5% of the world's human population.

The existing way of making influenza vaccine with chicken eggs is slow. However, faster ways of growing vaccine using cell lines can be much faster. Baxter Internation claims their CELVAPAN method could cut months off the time it takes to make vaccine.

Baxter has claimed its H5N1 vaccine could be ready within 12 weeks of an influenza outbreak, compared with 20 to 28 weeks if traditional methods are used.

In addition, cell culture does not suffer from the seasonality of egg-based production, which requires embryonated eggs.

Will Baxter's method get rushed into production if a new pandemic is starting right now?

CELVAPAN is manufactured in a cell culture-based system in Bohumil, Czech Republic, at one of the largest cell culture vaccine production facilities in the world. Vero cell technology uses a well-established cell line originally derived from African green monkey kidneys in 1962. A continuous cell line has been derived from these cells so that an unlimited supply of cells is available without the requirement of generating additional cells from animals.

10 years from now pandemic flus won't be a problem because we'll have much faster ways to manufacture vaccines. While vaccine production capacity has improved a lot in response to the avian flu and SARS threats we still are vulnerable to a new dangerous pathogen.

By Randall Parker    2009 April 28 11:56 PM   Entry Permalink | Comments (2)
2006 September 17 Sunday
Cell Culture Vaccines And Plasma Could Stop Bird Flu Pandemic

A pair of reports make the potential losses from a killer bird H5N1 flu pandemic look a lot smaller. First off, at the US military's Uniformed Services University of the Health Sciences some researchers have discovered that plasma taken from recovered flu victims in 1918 reduced the fatality rate of others infected by the killer 1918 flu.

USU faculty have discovered that a treatment for the Spanish Influenza pandemic may also be effective for current Avian Influenza patients. Navy Capt. Edward Kilbane, Army Col. Jeffrey Jackson and Navy Lt. Cmdr. Thomas Luke, are all alumni and faculty of the Uniformed Services University of the Health Sciences (USU). They, along with retired Navy physician, Capt. Stephen Hoffman, published their research Tuesday, Aug. 29, in the online edition of the Annals of Internal Medicine.

The four researchers analyzed medical literature reported during the Spanish Flu pandemic of 1918 to 1920. They found that transfusions with blood products from Spanish Flu survivors may have reduced the risk of death in seriously ill Spanish Flu patients.

The meta-analysis of these data show that treatment of patients in 1918 with convalescent whole blood, plasma or serum obtained from humans who had recovered from Spanish Influenza resulted in a reduced mortality of seriously ill patients by 50 percent.

If antibodies extracted from patients who recover from H5N1 avian flu would work against H5N1 in other people then each infected person who recovers could produce enough antibodies each week to help several people.

Another report argues that by switching to use of cell cultures to grow pandemic flu vaccine enough vaccine could be produced in the United States to treat the entire population of the US in a few months.

In a study led by University of Michigan professor of chemical and biomedical engineering Henry Wang and doctoral student Lyle Lash, researchers examined the economics of producing egg versus cell culture vaccines in the event of a flu pandemic. They found that training personnel to make cell culture vaccines in existing facilities is the only way to make enough doses to cover the United States in a short time without requiring huge capital investments to build new dedicated flu vaccine cell culture facilities.

...

The reasons to shift from egg to cell culture production are time and capacity, both of which are critical factors in responding to a pandemic, researchers said. It takes much longer to compile millions of hen eggs than it would to grow up existing cell lines from frozen vials, Lash said. While cell culture has a lower yield than egg culture, there is more existing capacity for cell culture than for inoculating and processing eggs.

"Based on existing dosages, we'd have enough doses in about 3 to 4 months to cover the U.S. with the system we propose," Lash said. Currently, it would take six months to make 250 to 300 million doses of pandemic flu vaccine for the United States. "What we're proposing could make 600 million doses in four months."

If you could manage to isolate yourself and your family for a few months starting at the very beginning of a pandemic then you could come out after those few months and get vaccinated. Also, plasma treatments would become available.

This all reminds me that I've yet to stockpile N95 and N100 face masks. They'd be helpful for occasional trips to the store. Otherwise I'll totally isolate myself if a killer pandemic hits.

By Randall Parker    2006 September 17 11:24 PM   Entry Permalink | Comments (4)
2005 October 22 Saturday
DNA And Cell Based Vaccines In Development Against Pandemics

British researchers call for accelerated development of DNA vaccines in case an H5N1 influenza pandemic breaks out in humans.

Researchers scrambling to combat a virulent form of bird flu that could mutate into a form easily spread among humans should consider developing vaccines based on DNA, according to British biochemical engineers. DNA vaccines, they say, can be produced more rapidly than conventional vaccines and could possibly save thousands of lives if a global influenza outbreak occurs.

A DNA-based vaccine could be a potent weapon against this emerging threat, particularly if enough conventional vaccine isn't available, according to Peter Dunnill, DSc., and his colleagues at University College London. However, they caution that any DNA vaccine should only be used as needed to slow the spread of the disease because the technique is largely untested in humans. The analysis appears in the November-December issue of the journal Biotechnology Progress, a co-publication of the American Chemical Society and the American Institutes of Chemical Engineers.

The avian virus, H5N1, has spread among birds throughout Southeast Asia and has been recently detected in Eastern Europe. The virus has killed more than 60 people in Asia since 2003 and forced the slaughter of millions of birds. There are no confirmed cases of human-to-human transmission of this flu, but that could change as the virus continues to mutate, Dunnill says.

If that occurs, current production facilities are unlikely to meet global demands for conventional vaccines in time to avert a pandemic, Dunnill says. But it might be possible to quickly produce a DNA vaccine by adapting the manufacturing processes of selected biopharmaceutical and antibiotic plants in countries such as the United States, China and India.

Current vaccine production facilities not only couldn't meet demand fast enough avert a pandemic. If a pandemic happens current production capacity will not be able to make enough vaccine for the industrialized countries for a year or two. For the whole world production of suffcient vaccine might take much longer. Just how big a hole we'd be in would depend on the size of the antigen doses needed in a vaccine against a pandemic influenza strain. But the egg-based method currently used for making influenza vaccine probably couldn't yield enough vaccine for the whole world for 2 or 3 years. Hence the need for faster and more easily scalable methods for making vaccine.

"A DNA vaccine is not a panacea, however it could be useful if the situation gets out of hand," Dunnill says. "But if we're going to try it, we need to move. You can't expect to walk into a production facility, hand over the instructions, and expect them to make it on the spot. It's going to take some weeks, and we really don't know how much time we have."

A DNA vaccine could be produced in as little as two or three weeks, Dunnill says. To do it, scientists would create a "loop" of DNA that contains the construction plans for a protein on the outer surface of the H5N1 virus. When that DNA is injected into cells, it would quickly reproduce the protein and trigger immunization in much the same way as a conventional vaccine.

In contrast, producing conventional vaccines from viruses incubated in fertilized eggs can take up to six months, which is too long to effectively prevent an influenza pandemic, Dunnill says.

Although no commercial influenza DNA vaccine is currently available, these vaccines have worked well in animals. However, human trials are still in the early stages so the safety and efficacy of these vaccines isn't fully established in people. But these trials could be accelerated, Dunnill says, particularly if the H5N1 virus eventually causes large numbers of human deaths and out paces the supply of conventional vaccine. In the worst case scenario, he suggests, using a DNA vaccine could be a "stop-gap" measure until enough conventional vaccine is available to corral the pandemic.

Given a working DNA vaccine a group at Cardiff University have developed a pain-less and easy delivery mechanism.

Researchers at Cardiff University have discovered a means of delivering DNA directly into skin cells, allowing it to be spread efficiently throughout the body.

The breakthrough could lead to mass immunisation campaigns being carried out by post. Patients would be able to administer the vaccine themselves by pressing a silicon chip embedded with 400 microscopic needles onto the back of their hand for a few seconds.

A painless small silicon chip placed on the skin would deliver the DNA vaccine into surface skin cells where the DNA would get expressed to make antigen that the body's immune system would make antigens against.

The new micro-needles are long enough to penetrate the skin but not to reach pain receptors.

They were designed to introduce a DNA vaccination directly into skin cells.

Vical has just got a DARPA contract to investigate methods for rapidly producing large quantities of DNA vaccine.

SAN DIEGO, Sept. 22 /PRNewswire-FirstCall/ -- Vical Incorporated (Nasdaq: VICL) today announced that it has been awarded funding for a one-year, $0.5 million project for the Defense Advanced Research Projects Agency (DARPA), of the U.S. Department of Defense. The award will fund feasibility studies of a new approach for rapidly manufacturing large quantities of DNA vaccines.

Conventional vaccine development and manufacturing methods require years of effort after the emergence of a new pathogen for production of even a single dose for testing. Current DNA vaccine development and manufacturing processes allow initial production of vaccines in as little as three months after selection of a gene sequence associated with a pathogen, but quantities are limited by the batch-processing capacity of available manufacturing equipment. Vical intends to use the funding to evaluate new methods that would dramatically reduce the manufacturing time and increase yields, allowing production of millions of doses in a matter of weeks.

French vaccine maker Sanofi-Aventis received a $97 million dollar contract from the US Department of Health and Human Services in April 2005 to develop a non-egg cell-based method of making vaccine in infected cells in large stainless steel vats. A number of other companies are also pursuing cell-based and DNA-based methods for rapidly scaling up vaccine production.

Sanofi is the first company to be awarded a U.S. government contract for developing a new method of vaccine production, but it is not the only drug maker experimenting with alternate methods. Crucell, which works on cell-based and DNA-based methods of vaccine production, has also licensed its technology to British drug maker GlaxoSmithKline (down $0.51 to $50.02, Research) and Swiss drug maker Roche (up $0.22 to $144.18, Research), according to Bernstein analyst Gbola Amusa, who projected that a non-egg production method could be on the market by 2008. PowderMed, a privately-held British company, is also developing DNA-based methods for vaccine production, while Philadelphia-based Hemispherx Biopharma (down $0.11 to $2.21, Research) is working on a cell-based method.

Acceleration of research and development of more easily scalable and rapid methods for making vaccine ought to be the top priority for preparations against an H5N1 avian flu pandemic. The technology developed will be useful for any flu pandemic and also for producing vaccines against a large range of other diseases.

By Randall Parker    2005 October 22 12:46 AM   Entry Permalink | Comments (2)
2005 October 02 Sunday
Finland To Vaccinate Entire Population Against Avian Flu

Finland's policy makers are taking a bold step against the threat of an avian flu pandemic.

In response to a recommendation by the World Health Organization, according to which the avian influenza pandemic threat is real, Finland is preparing to vaccinate its entire population against the disease.

The argument against doing this is that if H5N1 bird flu makes the mutational jump into easy transmissibility in human populations then that strain may be (probably would be) immunologically different than whatever H5N1 strain(s) Finland chooses to immunize against.

So then is the Finnish government wasting time and money? I can think of two arguments for why a preliminary vaccine might help. I'd really like to know if either or both arguments have any scientific merit: A) Partial immunity from a premature vaccine would reduce the lethality of an eventual pandemic infection and/or B) Vaccination by a premature H5N1 vaccine would reduce the size or number of a later vaccine dose using a more exact antigen target made to match an eventual pandemic strain (assuming such a strain will arise).

One reason put forward for why avian H5N1 influenza vaccine doses must be very large (see below) is that humans have few antibodies aimed at anything remotely like H5N1 since it is a bird influenza. Well, couldn't we treat the current strains of H5N1 as basically trainer strains to teach the human immune system about that category of influenza? Is there some reason to expect a future pandemic strain of H5N1 to be much more antigenically different from current H5N1 than human influenza strains are different from each other over a period of a few years?

If either of these arguments has merit then affluent folks who see avian flu as a big threat might want to start planning a medical tourism trip to Finland or to any other country that announces plans to vaccinate their entire population.

Recent vaccine testing for H5N1 bird flu found that 12 times the normal vaccine dose was needed for a good immune response against H5N1. That's very bad news. Assuming such a large dose size then current existing worldwide vaccine production capacity could make only 25 million doses per year against H5N1 influenza. By contrast when used against conventional human influenza strains world production capacity translates to 300 million yearly doses. The French vaccine maker Sanofi Pasteur is rumoured to be conducting trials using just 3.5 micrograms (as compared to the standard 15 microgram dose or 2 90 mch doses for H5N1) of H5N1 antigen plus an adjuvant compound to enhance immune response. If Sanofi Pasteur's trial works and all vaccine makers can follow the same approach then worldwide yearly production would effectively quadruple to 1.2 billion doses per year.

Current H5N1 test vaccines have to be taken as two large doses several weeks apart (and, yes, you would therefore be at risk of infection for those several weeks). The ability to produce much smaller single dose vaccines would greatly reduce the length of a pandemic, the death toll, and the size of the economic disruption. Therefore a lot potentially rides on a successful outcome of Sanofi Pasteur's trials.

70% of the world's flu vaccines are produced in Europe.

Most of the world's flu vaccine is produced in nine countries: Australia, Britain, Canada, France, Germany, Italy, Japan, the Netherlands and the United States. Europe produces 70% of the vaccines. And Europe's vaccine producers are worried.

Each nation on that list is a potential place to get a preliminary bird influenza vaccine before a pandemic hits. How about a medical tourism tour of European bird flu vaccine producing countries? Get about 3 or 4 different preliminary H5N1 vaccines and hope for a decent amount of partial immunity.

Canada's "pandemic readiness" fee contract for vaccine production sounds like the best idea I've heard for flu pandemics so far.

Canada, for example, recently signed a ten-year agreement with a manufacturer for its seasonal vaccine supply, and the country also pays an annual “pandemic readiness fee” which stipulates the company has the capacity to produce 8m doses of vaccine per month for four months.

Canada would still face an up-front delay of some months (3, 4, 5, 6 perhaps?) for developing the vaccine to put into production. But if their supplier can live up to that contract then any pandemic would last for less than a year in Canada. But my guess is that contract is based on the assumption that normal vaccine dose sizes would be used. So Canada's preparedness probably still depends on an optimistic expectation about dose size.

By Randall Parker    2005 October 02 09:24 PM   Entry Permalink | Comments (11)
2005 September 28 Wednesday
Hungary Could Make Half Million Flu Vaccine Doses Per Week

The length of a future dangerous influenza pandemic will be determned by the speed at which vaccines can be produced against the specific flu strain that emerges. For something like the H5N1 avian or bird flu speculative production of vaccines ahead of time might not help much because the bird flu virus is mutating a fair amount. Though vaccination against current strains would probably at least provide some degree of partial immunity and probably deserves more consideration than it is currently getting.

I'm going to start collecting information about vaccine production capacities around the world since those capacities will determine the length of a pandemic and therefore the number of lives lost and the size of the economic cost. Here's the first vaccine production capacity report I've found. Hungary could make a half million vaccine doses per week.

If a different strain of the virus becomes dangerous for humans, it would take Hungary eight weeks to produce the first 500,000 vaccines after receiving the virus from the WHO, and it could then make another half a million portions per week.

That puts their yearly capacity at about 25 million. One wonders how much they could scale up production during an emergency and how long the scaling up would take to implement.

I'd like to know whether the Hungarians are using a new type of vaccine production technology. The bulk of flu vaccine production today is done using fertilized chicken eggs and takes months. Are the Hungarians saying they can produce a half million doses each week? Or are they saying they can put a half million doses worth of fertilized chicken eggs into the process each week with the results coming out two or three or four months later?

I'd also like to know whether the report from Hungary assumes a vaccine dose size based on the newness of H5N1 in humans. A completely new strain of influenza requires a larger vaccine dose. I've previously read that new strains require double the dose and hence all influenza vaccine production capacity figures have to be reduced by a factor of 2 when discussing bird flu. Chris Spence, who writes an avian flu blog showed up on in the comments of one of my previous posts and painted an even bleaker picture of the dose size needed to handle H5N1 bird flu in humans.

The story with vaccine development is even worse. The current vaccine being tested and developed and in the U.S. based on the avian version of the virus (avian -> human, rather than human -> human) requires a very large dosage rate to create an immune response. Based on early testing, to create an immune response, a dosage had to be given of 90uL, rather then the normal vaccine level of 15uL. In addition, because we have no natural immunity to this virus, we need to have two vaccines given, a month apart, for a total dosage of 180 uL (90uL X 2). This reflects a total required dosage of 180uL which is 12 times the normal dosage. Unless studies using Adjutives and other methods to reduce the required dosage prove successful, our reported production capacity for flu vaccine in the U.S. of 90 million annual doses, is actually only a capacity of 7.5 million doses (vs a population of roughly 296 million or a 2.5% coverage rate). Add this to the likely low effectiveness of the vaccine (it is being produced based on the current strain directly from birds - the pandemic strain that spreads from humans to humans is likely to be significantly different), the effectiveness of the current vaccine may only be 20 - 40% effective (no one knows until the strain breaks out, but based on prior vaccines that were a poor match to the final virus). The world wide vaccine production capacity is currently 300 million doses, or 25 million at this higher dosage rate. With a world wide population of 6.45 billion. This would only cover 0.4% of the worlds population. Not very encouraging news.

Is the H5N1 vaccine production situation really that bleak?

What vaccine dosage size would be needed in an H5N1 pandemic? Also, are any new vaccine production technologies far enough along to provide hope for more rapid scaling up of vaccine production? Also, how rapidly could conventional influenza vaccine production technology be scaled up?

By Randall Parker    2005 September 28 08:17 PM   Entry Permalink | Comments (1)
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