Re: CIDRAP - THE PANDEMIC VACCINE PUZZLE
Kudos to Maryn McKenna and the CIDRAP group for putting together what I thought was an excellent and timely review of vaccine research. Of course a vaccine is only one aspect of proper planning for a pandemic but I would encourage anyone interested to read the entire well done and very readable series. I've picked out a few excerpts...
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct2507panvax1.html
THE PANDEMIC VACCINE PUZZLE
Part 1: Flu research: a legacy of neglect
after almost a decade of research, a safe, effective, affordable, and abundant vaccine against H5N1 flu remains disappointingly out of reach. The search for a human avian-flu vaccine that could be developed and delivered in time to short-circuit a pandemic has been dogged by multiple obstacles across many sectors.
HHS has allocated $3.2 billion of that to expanding vaccine capacity.
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct2607panvax2.html
THE PANDEMIC VACCINE PUZZLE
Part 2: Vaccine production capacity falls far short
The difficult reality is that, even if influenza science were perfect and research funding were abundant, achieving a widely deployable pandemic vaccine is currently out of reach. Chief among the reasons: The world lacks the manufacturing capacity to make enough vaccine to matter.
But the more difficult obstacle is not the time needed to produce vaccine?which newer technologies such as cell culture could shorten to some degree?but the amount of vaccine needed. Despite years of work, the grave mismatch between predicted demand and likely supply has yet to be solved.
The WHO analysis hides a number of highly optimistic assumptions, including zero glitches in production and 100% cooperation by regulators. But the greatest assumption may be that the newly produced pandemic vaccine would be distributed equitably to all comers around the globe. It is more likely that vaccine would never leave the countries where it is produced.
For the rest of the world, about 40% of the doses used in central and eastern Europe, 60% of the doses used in the western Pacific and Southeast Asia, and virtually 100% of the doses used in Latin America, the eastern Mediterranean, and Africa were imported from one or more of the nine vaccine-producing developed countries" (see Bibliography: Fedson 2003).
"If we really want to have surge capacity for pandemic vaccine, we have to invest in it like we do our oil reserves, or military reserve capacity," Osterholm said. "The facilities may sit for years before they are utilized. But the analogy is having an airport fire department in case of a plane crash: You hope never to use it, but you invest as though it were a possibility" (see Bibliography: Osterholm 2007).
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct2907panvax3.html
THE PANDEMIC VACCINE PUZZLE
Part 3: H5N1 poses major immunologic challenges
requires the use of reverse genetics to create a seed strain that will reproduce in eggs. Reverse genetics and the stringent pre-release testing that follows add a minimum of 6 weeks to the vaccine production process (see Bibliography: Wood 2007: Reference viruses).
Reverse genetics may be responsible for a phenomenon noted by several researchers: H5N1 does not reproduce well in vitro, a potentially major obstacle for vaccine production because it would greatly lengthen the manufacturing timeline .
Furthermore, when candidate vaccines have been produced from them, H5N1 and similar viruses have not done a good job of provoking an immune response.
Experts who reviewed the data during FDA deliberations on licensure agreed, signaling that they hoped for improved results as research advances. "There are numerous vaccines under development that are potentially better, if you will, than this vaccine. This is an interim vaccine," Norman Baylor, PhD, director of the FDA's Office of Vaccines Research and Review, said during the FDA hearing (see Bibliography: FDA 2007: Committee meeting transcript).
In addition, they fear the high dose?which at 180 mcg total is four times the total seasonal trivalent dose?could provoke an unusual rate of adverse reactions (see Bibliography: FDA 2007: Committee meeting transcript).
"I think this is our biggest scientific issue?that we are not sure what the appropriate surrogate for protection is
"It's important to understand that this choice of a 1:40 endpoint is not validated in any way as an actual assessment of protection against H5 in humans," Dr. John Treanor of the University of Rochester, principal investigator for the trial that produced the licensed H5 vaccine, said at the FDA licensure hearings.
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct3007panvax4.html
THE PANDEMIC VACCINE PUZZLE
Adjuvants are chemicals that are incorporated in some vaccines to improve response to the vaccines' active ingredient. Adjuvants make it possible to reduce the dose of antigen in a vaccine without dampening the immune response
H5N1 changed the risk-benefit ratio so that we are willing for instance to work with adjuvants, which may have theoretical risks but certainly may well afford tangible benefits. We're going to learn a whole lot about the immunology of protection that we haven't learned in the past" (see Bibliography: Monto 2007).
the need to seek regulatory approval for novel components in adjuvanted pandemic vaccines could prove a barrier to rapid market entry of formulas that look promising.
The most provocative news in dose-sparing has come in the past several months. In August, scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion; after the second injection, even the lowest dose of 3.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007). And in September, Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company's own proprietary formula induced EU-accepted levels of protection after two doses of 1.9 mcg.
Regulatory barriers loom
Like many other aspects of pandemic planning, adjuvants' ability to solve some of the challenges of preparedness will depend on how rapidly a pandemic arrives.
antigen-sparing pandemic vaccines may require a full Biologics License Application?the complete portfolio of testing and data, on both the product and the manufacturing facility, that is demanded of any new drug submitted for licensure and can take years to assemble (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines).
Regulators acknowledge that could stand in the way of, for instance, converting the already-manufactured vaccine in the national stockpile (which was purchased under the 90-mcg-dose license granted Sanofi Pasteur earlier this year but is held in bulk) to an adjuvanted vaccine that could be stretched much further.
Manufacturers have welcomed the government interest because negotiating combinations of components from different companies is fraught with antitrust and intellectual-property pitfalls.
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct3107panvax5.html
THE PANDEMIC VACCINE PUZZLE
Part 5: What role for prepandemic vaccination?
Most recently, the GlaxoSmithKline-backed team that described an acceptable immune response after two adjuvanted 3.8-microgram (mcg) doses found that three fourths of their subjects were protected not only against the clade 1 Vietnam virus on which the vaccine was based, but against a drifted clade 2 virus from Indonesia as well (see Bibliography: Leroux-Roels 2007).
The findings are not completely understood, though researchers agree that they make biological sense. Adjuvants stimulate the immune system in some manner that is broader than and different from the body's reaction to the antigen packaged with them. The discovery that adjuvanted flu vaccines may invoke cross-reactivity has generated tremendous excitement ?because that could allow production of at least partially protective vaccines well in advance of a pandemic's beginning.
Any vaccination that took place before a pandemic was detected would offer uncertain amounts of both benefit and risk.
"Extraordinary threats call for consideration of innovative strategies that, in less-threatening circumstances, might be dismissed," Bruce Gellin and Ben Schwartz of the Department of Health and Human Services' National Vaccine Program Office wrote 2 years ago.
Recognizing those hurdles, the European Centre for Disease Prevention and Control said in August that while it welcomes the development of prepandemic vaccines, it would not support administering them until a WHO declaration of pandemic phase 5 or 6, meaning significant human-to-human transmission is occurring or a pandemic is under way (see Bibliography: ECDC 2007: "Pre-pandemic" vaccines might offer protection but uncertainties remain).
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/nov0107panvax6.html
THE PANDEMIC VACCINE PUZZLE
Part 6: Looking to novel vaccine technologies
Because they contain live virus, live-attenuated vaccines provoke multiple types of immunity. In studies they have been shown to protect against both the strains from which vaccine candidates were derived and against drifted (slightly mutated) strains as well?characteristics that make them highly appealing to pandemic planners But their live-virus content is responsible for the vaccines' greatest potential danger: the possibility that they might lead to reassortment between the vaccine virus and circulating flu strains.
The promise of cell-culture production
The simplest but in some ways most challenging proposals for addressing the slow development of pandemic vaccines are ones that directly address the shortfall in flu antigen by radically changing production techniques.
Moving flu vaccine production from eggs to cell culture would simplify manufacturing in several key areas.
By dispensing with eggs, it would eliminate the need for putting a pandemic virus through reverse genetics, shaving 4 to 6 weeks off vaccine production. And because the vaccine virus is grown in giant industrial fermenters, it could offer a vast increase in production capacity?but only if manufacturers or governments make significant capital investments (see Bibliography: GlaxoSmithKline 2005, Novartis 2006) or manufacturers quickly convert the 2.5 million liters of cell-culture capacity (see Bibliography: FDA 2007: Committee meeting transcript) in use around the world for other pharmaceutical products.
The first cell-culture vaccine for seasonal flu, made by Novartis, was approved by European Union authorities in June (see Bibliography: Novartis 2007: Novartis gains European approval).
A refinement of the cell-culture strategy involves isolating the flu virus's hemagglutinin gene and using recombinant technology to express the hemagglutinin in insect cells grown in bioreactors. The main commercial proponent of this process, Protein Sciences Corp., claims it can halve the standard production timeline while delivering higher yields (see Bibliography: Lauerman 2007). The baculovirus-expressed recombinant product has been successfully tested for safety and immunogenicity (see Bibliography: Treanor, Schiff 2006; Treanor, Schiff 2007), Submission of a recombinant pandemic vaccine would follow approval of the seasonal vaccine, chief operating officer Manon Cox said at an FDA hearing earlier this year (see Bibliography: FDA 2007: Committee meeting transcript).
http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/nov0207panvax7.html
THE PANDEMIC VACCINE PUZZLE
Part 7: Time for a vaccine 'Manhattan Project'?
A chorus of calls to action
Calls have come from across the political spectrum for a more aggressive, better-funded, tightly organized research effort.
Redefining the problem
Those calling for a Manhattan Project?like effort say that what is needed is much broader than what NIAID or all of NIH could deliver. It requires active coordination among all the federal health agencies along with cooperation from congressional funders, plus parallel efforts in other countries. "Pandemic vaccine development has been viewed primarily as a vaccine problem that should be addressed with better science," Fedson said, "but fundamentally it is a global public health problem that requires better management" (see Bibliography: Fedson and Dunnill 2007: From scarcity to abundance).
And, they say, it is urgent that such an effort be established soon, because there is no way of predicting accurately when a pandemic might arrive. If it arrives soon rather than later, the lack of vaccine in most of the world will create a divide between haves and have-nots that could corrupt international relations long after the pandemic ends.
It is possible that failing to achieve a pandemic vaccine when it is needed?or even failing to confront in advance the possibility that supplies will fall short?could fracture international pandemic preparations just when cooperation will be essential.
