GSK announces avian flu vaccine trials

Seizing on yesterday's mixed results for Sanofi Pasteur's avian flu vaccine (which we wrote about in our last post), GSK announced today the launch of avian flu vaccine trials of its own. Here's Reuters report on the announcement and the GSK press release.

As we noted yesterday, the key problem with the Sanofi vaccine is the very high doses needed to generate a satisfactory immune response. GSK is optimistic that they won't have similar problems because of the addition of adjuvants, ingredients that amplify the immune system's response to a vaccine. One trial includes a common alum adjuvant, the other uses GSK's own AS04 adjuvant (which also is included in its HPV vaccine, among other GSK products). Both trials have enrolled approximately 400 volunteers.

Describing the AS04 adjuvant trial, the GSK press release explains...

"GSK is hopeful that a vaccine formulated with this novel adjuvant will further enable individual’s immune system to respond to different H5N1 virus strains, offering a broader protection against the threat of a pandemic. GSK’s novel adjuvant technology is also expected to further reduce the amount of antigen needed per dose, increasing the number of doses the company could make available worldwide."

Hope and expectation are both nice, but the data will be the final judge. Preliminary results are expected by the end of summer.

Questions of effectiveness surround avian flu vaccine

The March 30 issue of the New England Journal of Medicine reports on clinical trial results for the first-generation avian flu vaccine currently being stockpiled. The news? Not so good. Here's how the New York Times leads their story:

"A bird-flu vaccine being stockpiled by the government in preparation for a possible pandemic protects only about half the people who receive it, scientists are reporting. In addition, it must be given in such high doses that if a pandemic were to start soon, manufacturers could not begin to make enough vaccine for all who would need it."

You can read the full paper for yourself for free at the NEJM's site. The paper itself doesn't paint quite as gloomy a picture of the vaccine's prospects. Among other results, they report that it did not cause severe side effects among the 451 research subjects enrolled in the trial. Good news, yes, but that by no means assures a similar safety profile if/when it's administered on the order of millions of doses, as the history of vaccine development has shown repeatedly.

In fact, a potential ethical issue here is the all but certain lack of large-scale clinical testing of avian flu vaccines prior to their use in a pandemic. Testing of RotaTeq, the new Merck rotavirus vaccine, included a 70,000 person clinical trial, providing the kind of safety data that we almost certainly will not have for avian flu vaccines prior to needing them. Even if we had the time for such trials, by the time they were completed, the virus' continued mutation likely would have already rendered the vaccine in question ineffective. (Case in point, HHS has already announced plans to develop a 'second-generation' avian flu vaccine to replace the one being studied here. We discussed this in a previous post.)

The questions about this vaccine's effectiveness noted in the Times story and in an accompanying editorial in the NEJM differ from those we've pondered in the past (here, here, and here). There's no way of knowing with absolute certainty whether an avian flu vaccine (or any vaccine) trully provides protection against infection until those vaccinated are exposed to the virus.

As it would be wildly unethical to design a clinical trial in such a way, researchers rely on surrogate markers, such as the quantity of antibodies a vaccine produces in the immune system. More antibodies = greater likelihood of protection (generally). This clinical trial couldn't possibly answer the overall question of how the vaccine will stand up to a pandemic, yet it raised additional concerns over how well this vaccine can trigger the kind of activity in the immune system necessary to give it a decent chance against the virus.

More to come, no doubt...

Checking in on the Global HIV Vaccine Enterprise

As we've written previously, we're interested in the quest for a vaccine against HIV, what some consider to be the Holy Grail of infectious disease research. One of the most innovative aspects of HIV vaccine research is the creation of the Global HIV Vaccine Enterprise, a multinational consortium first proposed by leading researchers in 2003 and shortly thereafter supported by the G8 nations and the Gates Foundation.

Supporters of the Enterprise argue that it will foster collaboration, reduce dead-end experiments, and lead to more rapid progress in overcoming the significant scientific obstacles to a vaccine. Others wonder if consolidating much of HIV vaccine research under a large umbrella will stifle the creative ideas that sometimes, despite long odds, lead to breakthroughs. It's far too early to tell who's right, but if successful, the Enterprise model may have applications throughout vaccine research.

On Friday, the Chicago Tribune published a story about the initiative. No 'news' in the story, but a nice overview of the Enterprise and its rationale.

There was news regarding the Global HIV Vaccine Enterprise last week, though the announcement likely occurred too late for the Tribune story. Adel Mahmoud, the former president of Merck Vaccines, was named chief executive of the alliance, effective September 1. Here's the press release.

Phila. Inquirer weighs in on HPV vaccines

Today, the editorial page of the Philadelphia Inquirer offers its take on HPV vaccines with an editorial titled "Cervical cancer vaccine: Give it a fair trial." Voicing its support for the vaccine, the editorial questions the validity of concerns that HPV vaccination could lead to increased promiscuity among teenagers. They write,

"Without doubt, sexual abstinence is far and away the best course for teenagers. But the abstinence issue is mostly about values, urges and emotions - not about distant health risks that few teenagers would take seriously.

The sure harm from shelving an effective vaccine for cancer far outweighs the dubious harm that vaccination might do to teenagers' moral judgment."

You can read our previous posts this month on HPV vaccination matters here, here, and here. We'll be tracking editorials and op-eds on the vaccine here between now and June, when key decisions are expected as to licensure and recommended use. If you come across opinions in your hometown newspaper, let us know.

Increased need for veterinarians in public health efforts

In today's New York Times, medical reporter Larry Altman has this piece discussing the increased need for joint efforts by veterinarians and physicians to respond to emerging disease threats that are carried and spread via animals. Avian flu is not the only reason such collaborations are needed...

"The diseases are known as zoonoses because they affect animals primarily, and humans only incidentally. The AIDS, SARS and A(H5N1) avian influenza viruses and at least eight other infectious agents carried by animals have led to new and emerging human diseases in recent years."

"Preventing further outbreaks, participants said, will require a variety of measures, including more education about zoonoses among veterinarians and physicians; more integration of animal diseases into health plans; the creation of more laboratories to detect animal diseases; and possibly changes in the foods people eat and the animals they keep as pets."

Gates-sponsored effort working toward a new TB vaccine

For the second time in the last seven days, the Washington Post looks at issues related to new vaccine development. (Last Friday was this story on setbacks for VaxGen's anthrax vaccine, which we wrote about here.) Today's story highlights tuberculosis and the efforts of the Aeras Global TB Vaccine Foundation to develop the first new vaccine for the disease in over 80 years. An excerpt:

"Though nearly forgotten in rich countries such as the United States, the lung ailment sickens many millions of people every year and kills nearly 2 million of them. The 1921 vaccine, to this day the most widely used vaccine in the world, protects babies from the worst forms of TB but doesn't do much to cut the toll in adults. Backed by tens of millions of dollars from the Bill and Melinda Gates Foundation, Aeras is working on an improved vaccine that might finally banish the disease."

Here's the Aeras website. It's worth noting that 2012 is cited as the earliest date that the aforementioned vaccine could be widely available.

As is increasingly the case with any large-scale global health initiative, the Gates Foundation has played a central role in this project. Of particular interest is the model for vaccine development employed by Aeras, one that replicates that of the major vaccine manufacturers on a scale few private entities could match. The Post explains...

"Aeras, with $108 million in Gates money, has gone further than any of the other Gates-funded groups. Not only has it set up a pipeline, but it has now built a $10 million drug factory that will allow it to produce any vaccine that emerges from the far end of that pipe. Except for its nonprofit charter and its financing, Aeras is hard to distinguish from a small drug company."

In the past, a common complaint about the pharmaceutical industry has been their apparent unwillingness to invest in vaccine research for diseases most prevalent or most severe in the developing world. The thought has been that the potential profitability of such vaccines is too limited to make their development investment worthwhile. (The Merck and GSK rotavirus vaccines may partially dispel this perception, although their potential market in the U.S. and Europe is far greater than any vaccine against TB or malaria would be.)

If this Gates/Aeras TB initiative is successful (far too early to tell), it would signal the existence of a novel pathway to develop vaccines for diseases primarily of the developing world, irrespective of concerns over profitability. A story well worth following in the years ahead.

Update: China to release avian flu samples to WHO

Last week, we wrote about the unwillingness of Chinese health authorities to share their collected isolates of avian flu with the world community, potentially impeding work toward an effective vaccine in advance of a pandemic ("Chinese secrecy stalls bird flu vaccine").

Today, news that China has appeared to reverse course, agreeing to release approximately 20 live animal samples of the virus in the coming weeks. Voice of America, among others, has the story...

"World Health Organization officials say they expect China to deliver around 20 bird flu virus samples from animals soon. Their announcement Wednesday follows a long standoff in which Beijing had refused to turn over the samples that health officials say could help in the global battle against the disease.

WHO officials have been negotiating for months, trying to get the Chinese Ministry of Agriculture to hand over the live animal samples. Health officials say the dispute has resulted from Chinese academics not wanting to give up their research, partly out of concern that they and their country might not get credit for it."

It's anyone's guess at the moment how beneficial these samples (and hopefully those China agrees to share in the future) will be for efforts to track the virus' mutation, but there's no doubt that this is a positive development.

The challenges of polio eradication

Today, the New York Times launched on its front page a five-part series titled "On the Brink". The series will focus on diseases...

"...that are extinct in the developed world but stubbornly persistent in some poor nations. As the diseases hover on the brink of eradication, doctors and scientists face daunting obstacles as they struggle to finish the job."

Today's piece is an extensive, 4,000 word examination of the quest to eradicate polio worldwide. We've written previously about polio eradication efforts. The Times piece elaborates on how rumored safety concerns, public suspicions of government motives, and questions over the continued necessity of vaccination have hampered the push toward eradication. While the story discusses only polio in the developing world, these objections sound all but identical to common criticisms of any vaccination campaign, developing world or otherwise. An excerpt:

"Since [1988], some two billion children have been vaccinated, cutting incidence of the disease more than 99 percent and saving some five million from paralysis or death, the World Health Organization estimates.

But six years past the [2000] deadline [for polio eradication], even optimists warn that total eradication is far from assured. The drive against polio threatens to become a costly display of all that can conspire against even the most ambitious efforts to eliminate a disease: cultural suspicions, logistical nightmares, competition for resources from many other afflictions, and simple exhaustion. So monumental is the challenge, in fact, that only one disease has ever been eradicated -- smallpox. As the polio campaign has shown, even the miracle of discovering a vaccine is not enough."

It's an excellent piece that offers a glimpse at the staggering complexity of mounting an effective vaccination campaign on a global scale.

Also of note is this sidebar piece on the merits of disease eradication as a public health goal.

FDA nominee von Eschenbach on HPV vaccines

Dr. Andrew von Eschenbach, recently nominated to serve as director of the Food and Drug Administration, delivered the keynote address at the national conference of the Association of Health Care Journalists yesterday in Houston. Von Eschenbach is currently the acting director of the FDA (following Lester Crawford's abrupt resignation last September) as well as director of the National Cancer Institute.

As the Houston Chronicle reports, von Eschenbach declined to offer specifics of his vision for the FDA because of his pending confirmation hearing in the Senate. (The FDA has generated considerable criticism and controversy due to its handling of the contraceptive Plan B, which will almost certainly receive more attention from the Senate than anything vaccine-related).

Von Eschenbach did respond (generally) to questions regarding the status of HPV vaccines as well as the broader topic of the Bush administration's positions on science. On HPV vaccines...

"Von Eschenbach...would not talk about where the vaccine is headed in the approval process. But he hailed its 'great promise for the prevention of one of the most significant killers of women' and said it 'fits very well' into his anti-cancer agenda."

On science vs. ideology:

"Asked about the criticism that the Bush administration makes health care policy based on ideology rather than science, von Eschenbach said medical progress can't be removed from 'an ongoing societal discussion.' But he added that he has never felt constrained by the administration from following the scientific path."

Major setback for VaxGen anthrax vaccine

From today's Washington Post:

"The government's $1 billion effort to develop a new anthrax vaccine has run into difficulty, with the company in charge of the project reporting failure in a major human test and falling at least a year behind schedule.

Officers at VaxGen Inc. of Brisbane, Calif., said in interviews that they believe they have isolated the problem with their vaccine and are well on their way to fixing it. But they acknowledged that they have no hope of meeting a deadline to deliver 25 million doses of the vaccine into a national stockpile by November and will default on their contract with the government unless it grants an extension they have requested."

As the story notes, this setback is only the latest for activities related to Project Bioshield. Most large vaccine manufacturers have stayed away from the program, citing concerns about profit limitations and potential damage to their reputations if problems are encountered fulfilling contract terms. Thus, the work has largely fallen to smaller outfits such as VaxGen that lack the track record of Merck, Sanofi, and GSK, for example. In fact, seeing an opportunity to fill this void, VaxGen touts its 'biodefense business model' on its website. (Oddly, there's no mention in the business model of high-profile failures such as this.)

According to the Post, government contracts to VaxGen for anthrax vaccine work approach $1 billion. Today's news means that 2008 or 2009 is the earliest that a vaccine could be delivered.

In the meantime, the only anthrax vaccine available is an older product made by Bioport, a subsidiary of Emergent Biosolutions. As its FAQ notes, all of Bioport's vaccine production is owned by the U.S. military. There was some controversy a few years back when members of the military expressed reluctance at receiving the vaccine due to safety concerns. In response, the Department of Defense has this impressively-designed site that outlines their positions on the importance of military vaccinations and the safety of the Bioport vaccine.

Update, 10:31 PM: Perhaps not surprisingly, VaxGen took issue with much of today's Washington Post story. Here's a press release from their CEO with responses.

More problems for Chiron vaccines

News today that Chiron has recalled and withdrawn one of its measles, mumps, and rubella vaccines, Morupar, due to concerns over rates of adverse events. Here's the Chiron press release. The AP story, courtesy of the Washington Post site, explains...

"Italy determined five patients immunized with Morupar suffered adverse reactions, including fever and swelling of the glands, commonly associated with the vaccine, Marquiss said.

The same pattern hasn't been cropping up with MMR vaccines made by two other manufacturers, prompting the Italian Medicine Agency to order a withdrawal of Chiron's product from the market to protect the public's health."

It should be noted that this news has no direct impact on vaccination in the U.S., where the recalled vaccine is not licensed. (The only MMR vaccine available in the U.S. is this one from Merck. Whether it's wise to have only a single manufacturer for a universal vaccine is a topic for another post.)

Indirectly, however, today's news -- the sequel to their flu vaccine debacle in 2004 -- should raise alarms worldwide over Chiron's overall competence. At this point, it may be worth taking a closer look at how greatly Chiron should be relied upon to meet future vaccine needs, particularly with respect to avian flu. Just last month, in fact, Chiron received an extension from the U.S. government to deliver the (1st generation) avian flu vaccine for which they received a $62.5 million contract last October.

New England Journal piece on HPV Vaccines

Judging from the early traffic to our site from search engines, it's clear that there is significant interest in the ethics of HPV vaccines. As we've written previously here, we share your interest and expect the topic to explode this spring when key decisions and recommendations from government committees are anticipated. We'll be monitoring developments closely and expect to post often on this topic, likely more frequently than on any other.

In the meantime, the current issue of the New England Journal has this piece (for free!) that sets the stage for the months ahead. It covers virtually identical terrain as our earlier post on HPV vaccines (likely because we both based our reviews on the same presentations at last month's ACIP meeting). Nevertheless, the piece is an excellent, comprehensive look at where we are and where we're headed with HPV vaccines. It is well worth a read.

News that 'low-cost vaccine' may not be an oxymoron

The Financial Times has this story titled "Low-cost meningitis vaccine may be available in three years." Good news indeed, but if we read all the way to the third-from-last sentence in the story, we learn that the only 'news' is that phase I trial data for this vaccine candidate is positive, making the three-year prediction an optimistic (some might say best-case) scenario. Here's the press release from the Meningitis Vaccine Project, a Gates-funded consortium spearheaded by WHO and others.

Of course, anyone is free to issue a press releasing trumpeting the importance of their work, but it's an open question whether phase I trial results truly merit the media coverage they often receive. Given the years of additional research necessary and the high likelihood of failure along the way, such reports may only add to public confusion amid an already complex vaccine landscape. For this reason, you won't often see coverage of phase I vaccine trials here.

Why the exception this time? This passage in the FT story stood out:

"...The initiative would mark the first time a vaccine had been developed for and within the developing world, with an agreed low-cost price that was sustainable and profit-making for the manufacturer. It also marks a ground-breaking approach to developing the new medicines cheaply by using researchers from poorer countries, at a time when large western pharmaceutical groups claim it can cost $800m or more to produce drugs and vaccines.

By contrast, he said the Meningitis Vaccine Project was on budget to meet its objectives of developing, licensing, testing and introducing the vaccine in the period 2001-2011 for just $70m."

If this effort is ultimately successful (it's far too early to tell), it would mark a tremendous achievement for vaccines for the developing world.

There's no dispute that new vaccines against rotavirus and HPV would most greatly benefit developing countries, where the number of deaths caused by the viruses dwarf those in the U.S. and Europe. Sadly, however, the prices of these vaccines will limit their availability greatest in the parts of the world needing them most. With 2.1 million vaccine-preventable annual deaths (most of which involve much older and much cheaper vaccines), funding a new rotavirus series with a sticker price of $187.50/child would seem to face any number of challenges.

HHS Update on Avian Flu Preparations

HHS Secretary Michael Leavitt released an update today on U.S. preparations for a potential pandemic. The PDF is available here. After a sobering (but accurate) introduction assessing the current status of the virus and its westward spread, vaccines receive significant attention in the report.

One interesting piece of information appears in the pie chart on page 2 showing funding allocations. It notes that HHS was appropriated $3.3 billion for pandemic flu activities during the current fiscal year. Of that amount, nearly $1.8 billion (54%) has been allocated to vaccines. That’s more than the amount given to antivirals, state and local preparedness, medical supplies, surveillance, lab capacity, risk communications, and international activities combined. Look for comments in the next few days from constituencies in the medical community expressing concern over this distribution of resources, particularly among state and local public health officials.

Of the 12-page document, nearly 3.5 are devoted to vaccines. It appears to be a thorough, honest assessment of where we are regarding vaccine development and the many unknowns moving forward (which we’ve discussed previously here and here).

One statement in the report, while not new, should remind us of the many ethical issues regarding vaccine safety, manufacturer liability and the limits thereof, and the potential consequences of large-scale immunization efforts that could surface in a worst-case scenario…

“If a pandemic occurs prior to licensure of a vaccine, the FDA can use its Emergency Use Authorization authority to permit the use of unapproved products (or to permit unapproved uses for previously approved products) if there’s a reasonable belief the products may be effective and if the benefits would outweigh risks.”

More to come, no doubt.

The future of 'cancer vaccines'

Even though the phrase 'cancer vaccine' is a bit misleading, the HPV vaccines on the horizon will likely call attention to other cancers linked closely with viruses and bacteria. In theory, vaccines could be able to reduce the incidence of these cancers just as HPV vaccines appear to prevent most cervical cancers.

Today's Telegraph reports that Cancer Research UK has recently explored the topic. Their key findings:

"One in 10 cancers could be prevented by vaccines and they estimate that a quarter of cancers in the developing world are triggered by a handful of infections."

"The global number of virus-associated cancer accounts for more than 1.8 million cases of cancer each year - which is around 18 per cent of all new cancer cases worldwide."

The key contributors to this number are cervical cancer and some types of liver cancer (for which HPV and Hepatitis B vaccines are already available or will be soon). Less prevalent viral or bacterial-related cancers include cancer of nasal passages, some lymphomas, rare forms of leukemia, and many cases of stomach cancer, the story notes.

"China secrecy stalls bird flu vaccine"

The Australian has the latest on the apparent unwillingness of the Chinese government to cooperate with international surveillance efforts of avian flu. A greater concern is their refusal to share isolates of the virus, making it more difficult to monitor the virus' rate of mutation as well as to develop maximally effective vaccines in advance of a potential pandemic. The story explains:

"More than 90 people have died as the disease has spread from China to Europe and Africa. Yet bureaucrats in Beijing have only just agreed to share samples of live viruses after refusing such information to the international community during more than 30 outbreaks of the H5N1 virus.

Their reasons appear to have been an instinct to monopolise information and resentment that Chinese scientists were not credited for research published in an American academic journal."

It's safe to say that this topic is part of a much larger political/diplomatic situation extending well beyond avian flu. For our focus, however, we've written previously that the development of a highly effective vaccine in advance of a pandemic is already an uphill battle. Without complete access to viral isolates worldwide, the task becomes all the more difficult.

Encouraging news about worldwide measles vaccination

From ABCNews.com:

"A global immunization drive has cut measles deaths by nearly half during the last six years, the World Health Organization and United Nations Children's Fund said Friday.

Deaths from measles dropped from 871,000 in 1999 to an estimated 454,000 in 2004, according to the UNICEF and WHO report, marking a 48 percent decrease in fatalities suffered from one of the most contagious diseases known."

A tremendous achievement, and a testament to the effectiveness of sound public health interventions and robust vaccination campaigns. Still, the potential exists for even greater victories over measles in the years ahead. Putting these global numbers in context, according to this CDC data, the total number of measles cases (not deaths) in the U.S. in 2005 was a mere 63, thanks to 40 years of vaccination.

On the road with Bill and Melinda Gates

Today's Financial Times has a lengthy profile of Bill and Melinda Gates and their well-known philanthropic work. As it does at their foundation, vaccines are featured prominently in the story...

"Gates’s money also helped to develop a special ink for the labels of vaccine vials that changes colour at higher temperatures to show health workers when the vaccine has been spoilt and should not be used.

Both these simple but important technological developments have been supported by the Global Alliance on Vaccines and Immunisations (GAVI), a group set up with strong pressure from Gates, comprising representatives from governments, drugs companies and charities, that picked up the baton on immunisation in 2000 at a time when the large-scale campaigns of Unicef and the World Health Organisation were running out of steam.

GAVI is Gates’s response to criticism that he is obsessed with “blue sky” scientific research: supporting academics and pharmaceutical groups to develop vaccines and drugs for diseases such as HIV, malaria and tuberculosis which face such funding and scientific obstacles that they will take years to come to fruition, and may never prove successful."

As the story later explains, this approach too has been criticized by those believing funds could be better spent making proven therapies more widely available. Either way, it's hard to argue that any group has more influence than the Gates Foundation in shaping the future of global health.

Meanwhile, on the other side of the world...

While those of us in the U.S. and elsewhere debate 'behavioral disinhibition' and the effects (or lack thereof) of vaccine preservatives, this story notes that simply organizing an effective polio vaccination campaign is the focus of government officials in Nigeria. Despite being off the U.S. radar for decades (with the exception of a few cases among those unvaccinated), polio is still a concern in many parts of Africa and Asia, nowhere more so than Nigeria, according to this WHO site.

The story from Nigeria explains that government efforts for widespread polio vaccination (and hopefully, eradication) face a number of challenges. Chief among them? What else, controversies over vaccine safety.

No news on the HIV vaccine front, but a story anyway...

This CNNMoney.com story today on HIV vaccine research has little news value. Its thesis seems to be that an HIV vaccine would be wonderful news for the pharmaceutical industry (nevermind mankind). Backed by a handful of quotes from industry analysts, the author states that a vaccine...

"could bring in blockbuster sales for the companies behind it, save lives, and possibly even improve Big Pharma's battered image, all at the same time."

Even for a business website, it seems as though the issue of 'saving lives' is getting short shrift. Overall, despite several analyst quotes noting that a safe and effective HIV vaccine is years away (if ever), its descriptions of phase II and III clinical trials still sends the impression that we're closer to a vaccine than anyone working in the field believes.

This post isn't intended solely to criticize the story and its author (although his reference to Tamiflu as an "influenza vaccine" slightly hurts his credibility). Rather, it is a good example of the difficulties of accurate, sound coverage of vaccines in the media, particularly when reporters -- especially non-science reporters -- must rely on a few quotes from 'experts' to guide their story. A piece such as this is harmless, but when controversies surface regarding vaccines, such coverage can be problematic. We'll be paying special attention to this phenomenon in the weeks and months ahead.

Finally, a note that the quest for an HIV vaccine and the ethics thereof are special interests of the Ethics of Vaccine project. While other vaccine-related issues are more immediate concerns to society (avian flu, supply shortages, HPV, safety, etc.), the potential benefits of an HIV vaccine are immeasurable. We're interested in the work underway worldwide to make that potential a reality.

GSK submits cervical cancer vaccine for EU approval

We haven't yet posted about Merck's and GSK's vaccines against human papillomavirus (HPV), a sexually transmitted infection best known as the cause of cervical cancer (among other effects). By June, however, this will be the biggest vaccine ethics issue getting public attention.

A quick summary of where we stand today for those not following the developments closely... Both Merck (Gardasil) and GSK (Cervarix) have HPV vaccines nearing licensure. There are over 100 subtypes of the virus, but 2 are responsible for about 70% of cervical cancers. Both vaccines provide protection against these HPV subtypes. The Merck product also includes 2 additional subtypes that are the leading causes of genital warts in both males and females. As a result, both genders could directly benefit from Merck's vaccine, while the GSK product will target only females.

In the race to be the first on the market, Merck is in the lead, having submitted licensure applications in the U.S. and EU in December '05. Today's news courtesy of Reuters is that GSK submitted for EU approval of Cervarix. A decision is not expected for about a year. Their U.S. application is even farther behind; it's not expected until late 2006.

The reason why June is important is that two events scheduled for that month will determine the fate of Merck's Gardasil -- likely FDA approval early in the month followed by a recommendation from the CDC's Advisory Committee on Immunization Practices a few weeks later.

Why the likelihood of controversy? Several groups -- notably the Family Research Council -- have already expressed concerns about mandating HPV vaccination as a requirement for school entry. Why? 1) HPV is sexually transmitted. 2) To be maximally effective, the vaccine should be administered to pre-teen girls (age 11-13, perhaps as young as 9). 3) A key concern among some of these groups is that vaccinating girls of this age will encourage sexual activity -- a phenomenon known as 'behavioral disinhibition'. (It should be noted that there's no evidence that human papilloma virus is much of a factor at all in teens' sexual behavior -- factors such as pregnancy, religion, and risk of HIV dominate.) 4) These decisions should be left to families, they argue.

The FRC has tempered their position compared to comments made in this Fortune piece last October previewing the debate. Rather than broad opposition to the vaccine in principle, their key objection at this point is mandating vaccination for school attendance rather than leaving it a parental decision. The battleground is set for the June ACIP meeting and subsequent decisions by state departments of health.

The topic is more complex than this short preview allows. While it isn't on many people's radars just yet, the Fortune piece was right in dubbing it "the coming storm". We'll stay on top of it.

Mismanagement straight out of Central Casting, literally

The Los Angeles County Board of Supervisors will investigate how federal bioterror funds were spent after a report in yesterday's L.A. Times. Here is today's follow-up (registration required)...

"These expenses included $57,045 to hire extras from Central Casting to participate in a 2004 smallpox vaccination drill, along with gift bags to thank the paid actors and volunteers. The county also spent $128,000 on promotional items such as flashlights and letter openers, and $170,000 to train health department staff on how to put together videos to be viewed online. Two videos have been produced, neither of which focuses on bioterrorism."

Extras from Central Casting? Promotional letter openers? Hardly a ringing endorsement of the judgment of the disaster-preparedness folks in L.A.

"The face that helped alter the nation's flu policy"

While RFK Jr. decries last month's ACIP recommendation to expand flu vaccination to include children between 6 months and 5 years (yes, because of thimerosal), today's Washington Post presents the sad story of the family of a 4-year old girl who died from influenza, prompting her parents to advocate for wider vaccination. An excerpt...

"As he waited his turn at the microphone, in an Atlanta auditorium filled with doctors and scientists, Gary Stein wondered whether what he had to say would make much difference. These were the experts, he realized, the people who spend a lifetime studying viruses and vaccines. They already knew all the facts, the statistics.

Still, they didn't know 4-year-old Jessica.

So Stein began talking, as a father who once had a little girl with hair the color and shimmer of champagne, a child who loved dress-up and Barbies and who was as healthy as they come until the day in January 2002 when she caught the flu. Less than 72 hours later, she was dead. Stein thought he could get through the main points of his remarks without stumbling. But as he stood before the federal Advisory Committee on Immunization Practices, explaining how his Falls Church family had been devastated, he choked up."

Very sad, but a must-read. Reading it side-by-side with RFK Jr.'s piece, it's hard to believe both authors are discussing the same decision by the same group about the same vaccine. (Without wading too far into the murky depths of the thimerosal debate, it's worth noting that central to earlier arguments about its safety were concerns about the total amount of thimerosal administered from all vaccines together. Now that flu vaccine is the only pediatric product containing it, the position seems to be that any thimerosal is unacceptable.)

One can assume that Jessica's story alone did not persuade ACIP to change the flu vaccine recommendation, but, amid debates and controversies, it reminds all of us of the real-life consequences of infectious diseases and immunization policy.

NIH/CDC working on 2nd avian flu vaccine

At the National Immunization Conference in Atlanta, HHS secretary Michael Leavitt announced today that the development of a second avian flu vaccine has begun, this one on a more recent isolate of the virus. CBSNews.com has the story.

The 'original' vaccine is based on a 2004 sample of avian flu from Vietnam. The U.S. government has already spent $250 million for 8 million doses through contracts with Sanofi Pasteur and Chiron, the story notes. The cycle of vaccine development announced today involves a 2005 isolate from Indonesia. As we've written previously, the question no one can answer is how effective (if at all) earlier vaccines will be against the eventual 'pandemic' strain of avian flu, whenever (or if ever) it arrives.

Ultimately, there's agreement in the scientific community that the only vaccine sure to be effective against a pandemic strain is one developed only after it arrives, requiring a minimum 6-month wait for any vaccine and all but certain supply shortages. At this point, the hope is that these vaccines currently in production will provide some measure of protection in the meantime, if necessary.

The question for public health experts and health economists is whether a semi-annual, $250 million payout for vaccines that may or may not be effective is a sound use of resources as part of preparations for a pandemic. For bioethicists, in addition to the host of issues relating to the allocation of scarce resources, etc., this announcement adds a new wrinkle to consider: If/when a pandemic arrives, it's now possible that several 'generations' of vaccine will be available, with newer generations progressively more effective against the virus than earlier ones. How should this be handled? A national triage system? A roll of the dice based on which manufacturer your physician/hospital/state purchases vaccine from?

Promising data for GSK's otitis media vaccine

The CNN.com story was one of many in the past few days reporting favorably on GSK's vaccine against S. pneumoniae and H. influenza, the two leading causes of acute middle ear infections...

"The vaccine, called Streptorix, is currently being tested in ongoing Phase III clinical studies.

Researchers at the University of Defence in the Czech Republic tested the vaccine on nearly 5,000 infants and children under the age of five and said the vaccine reduced the frequency of infection by 65.5 percent.

'This study showed a statistically significant and clinically relevant reduction in episodes of acute otitis media," Dr. Roman Prymula, who headed the Phase III study, reported in the March 4 edition of Lancet.'"

The paper referenced has the catchy title "Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pnemoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study". (Lancet, 4 March 2006 (367):740-748.)

Licensure, however, is likely still a long way off: GSK plans to seek EU approval is 2007, with US approval coming at an unspecified date thereafter.

"Bird Flu Won't Wait"

In today's New York Times, Dartmouth Medical School professor Kendall Hoyt argues for a fundamental rethinking of the way vaccine development is structured as part of public health preparations for emerging biological threats, such as SARS and avian flu...

"[The current system] is less sensible, however, for many other threats, for two reasons. First, the number of pathogenic threats far outstrips our drug development resources. Second, epidemiological forecasting and intelligence about such threats are unreliable: witness the vaccination campaigns against botulinum toxin in World War II, swine flu in 1976, anthrax in the 1991 gulf war and smallpox before the Iraq war, which all addressed threats that failed to materialize. Creating stockpiles of vaccines for high-consequence pathogens is important. Beyond those, however, it's wiser to build a system that will allow us to react quickly to rapidly evolving or unexpected biological threats."

His suggestion: a 'bug to drug' program that could more easily adapt to the presence of new pathogens, creating new vaccines more quickly and ensuring adequate production capacity if/when needed.

More on thimerosal...

With a headline sure to amaze those who don't read the full story, the MetroWest Daily News (part of the Boston Herald family) proclaims, "Study links autism, vaccine." If this were even the least bit true, one suspects the MetroWest Daily News wouldn't be the only media outlet covering the story.

Rather, the story here is in reference to a paper published in the Journal of American Physicians and Surgeons titled "Early Downward Trends in Neurodevelopmental Disorders Following Removal of Thimerosal-Containing Vaccines."

The story explains:

"Autism diagnoses have dropped nationwide since mercury was removed from most childhood vaccines, according to a new study that some say lends credence to charges that vaccinations were responsible for a huge increase in autism cases. "

The paper in questions uses state and federal databases that track autism prevalance as well as VAERS, the Vaccine Adverse Event Reporting System. All of these sources have significant data reliability concerns, which, to the newspaper's credit, are noted in the story.

For example, adverse events can be reported to VAERS by anyone and are not verified for accuracy. This paper in Pediatrics (subscription required) -- Goodman, M.J., and Nordin, J. "Vaccine Adverse Event Reporting Source: A Possible Source of Bias in Longitudinal Studies." Feb. 2006; 117: 387-390 -- finds that most thimerosal-related reports to VAERS were directly related to pending litigation. The authors specifically warn researchers attempting to use VAERS data for studies such as the one above about the serious questions regarding its reliability.

RFK Jr.'s latest on thimerosal

Over at The Huffington Post, Robert F. Kennedy Jr. declares that it's "Time for the CDC to Come Clean" about the events leading to the decision in 1999-2000 to remove thimerosal from childhood vaccines. An excerpt:

"But newly released documents show that behind the scenes CDC was quietly discouraging Thimerosal's removal. In a July 1999 letter, vaccine producer SmithKline Beecham tells CDC that it is ready to produce non-Thimerosal DTP (Diptheria/Tetanus/Pertussis) vaccines immediately and has sufficient inventories to supply the entire U.S. market during the remainder of 1999 and the first half of 2000, by which time other vaccine manufacturers would have their Thimerosal-free DTP vaccines on line.

Thimerosal-laden DTP vaccines containing 25 micrograms of mercury apiece were then being administered to American infants at two months, four months and six months -- far exceeding EPA's recommended safe level for mercury. Had CDC accepted SmithKline's offer, it could have immediately reduced the mercury exposures to vaccinated six-month-old children by 40%.

However, in November, CDC mysteriously sent a letter back rejecting SmithKline's offer. Then, on July 14, 2000 CDC published a deceptive press release promising to require that all vaccines be Thimerosal-free as soon as "adequate supplies are available." This was a full 12 months after the agency had denied SmithKline's proposal.

"If CDC were basing its decision on safety alone, it would have taken SmithKline up on its offer. That's a no-brainer," said a federal health official who requested anonymity. "So there were other considerations beside safety that were guiding their decision making."

Among these "other considerations" were CDC's important concerns for the preservation of the vaccine program, a bureaucratic impulse for self-preservation, and protecting the economic interests of its vaccine industry friends."

While the thimerosal/autism stories have generally faded from the media spotlight (except for a few places, such as Imus, etc.), RFK Jr.'s post and many of the comments that follow it illustrate how strong the passions remain among those certain that a link exists and that the government and vaccine industry covered it up for financial gain.

There's little use reviewing here the arguments of both sides in this debate. What all could probably agree on is that the CDC decision to remove thimerosal in 2000 sent a mixed signal, since the evidence then (and now) cited by the medical community continues to show zero evidence of a link to autism. 'If the evidence is so clear, why call for its removal?' is a reasonable question to ask. What seemingly was an attempt to end the controversy by removing a non-essential ingredient has actually had the reverse effect, increasing skepticism and thoughts of conspiracy among those inclined to think in such a way. Years later, the controversy continues to simmer in many, as RFK Jr.'s comments illustrate.

GSK rotavirus vaccine approved by EU

Rotarix, the GSK rotavirus vaccine, received EU approval Monday. Forbes, among other places, had the details.

While GSK's vaccine is out in front on the international stage, it's yet to be licensed in the United States. RotaTeq, the rotavirus vaccine from Merck, was licensed by the FDA in December. As was widely reported last week, CDC's Advisory Committee on Immunization recommended routine vaccination with RotaTeq for all newborns at 2, 4, and 6 months. Here's the Washington Post story.

For those confused by news accounts of vaccines in development, similar products from competing manufacturers, and the maze of regulatory steps required in the U.S., the American Academy of Pediatrics has a very useful table on its website that provides the trade name, target, manufacturer, age range, licensure status, and AAP/ACIP recommendations (if any) for vaccines recently approved or currently in the approval process. The page is updated regularly and is a great resource. A link has been added on the right of the page.