HPV Roundup: Gardasil safety worries, Cervarix FDA delays, more on mandates

There's been a flurry of media coverage this week about possible safety issues related to Gardasil. It appears that the attention was initiated by this report released by Judicial Watch, the conservative watchdog group. Like its previous reports alleging numerous deaths and illnesses caused by vaccine, this Judicial Watch report is based on unconfirmed submissions to VAERS, the government's clearinghouse for reports of possible vaccine-related adverse events. Reports to VAERS -- widely described as a 'hypothesis-generating mechanism' -- are later examined by government officials to determine what, if any, role a vaccine may have had in the reported condition.

Numerous other outlets have raised questions about Gardasil's safety in the past few days, most notably this CBS News story by Sharyl Attkinson, the media member who is increasingly at the forefront of reporting on alleged vaccine risks. Other media outlets examining the topic include CNN and WebMD.

In the meantime, officials from CDC and FDA have assured the public that the vaccine remains safe and effective and that reports of possible adverse events will continue to be investigated. Merck responded similarly yesterday, noting the limitations of reports made to VAERS.

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Meanwhile, it appears that the U.S. head-to-head battle between Gardasil and GSK's Cervarix will most likely be delayed until late 2009. Last week, the Wall Street Journal and Reuters, among others, reported the GSK announcement of its timetable for submitting additional trial data requested by FDA. Here is the GSK press release. It notes that Cervarix is already approved in 67 countries, including the E.U., but it's no secret that the U.S. market is by far the most lucrative, as Merck's sales figures from earlier this year illustrated.

From a business standpoint, this is decidedly good news for Merck, as it extends its head start in the U.S. (The news has not all been good, however, as it was announced late last month that Merck's application to expand the indication for Gardasil for women through age 45 will face additional scrutiny and delays. Here's a story from Reuters and the Merck press release.)

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In other news, two papers have recently been published in academic journals on HPV mandates (joining a growing literature on this topic -- including papers by Schwartz, et al., Colgrove, and Zimmerman.) One paper, "Assessing Mandatory HPV Vaccination: Who Should Call the Shots?" (Javitt, et al.) appears in the Summer 2008 issue of the Journal of Law, Medicine & Ethics (subscription required). In short, the authors conclude, "...Mandating HPV vaccination at the present time would be premature and ill-advised."

Also, the May 2008 Harvard Law Review published a paper titled "Toward a 21st Century Jacobson v. Massachusetts (pdf), alluding to the 1905 case that is widely seen as the foundation for state public health powers. The authors argue that a distinction should be drawn between vaccines that are 'medically necessary' (such as smallpox) and those that are 'practically necessary' (such as hepatitis B and HPV, for which other preventive measures are available but not widely used). The paper suggests that current law and policy fail to acknowledge the implications of this distinction.

Avian flu: GSK vaccine contracts; NIH studying future pandemic strains

August brought a fair amount of news from GSK regarding their pre-pandemic influenza vaccine. At the start of the month, the company announced a new order from HHS for an additional 22.5 million doses of its avian influenza vaccine (in addition to the 5 million doses ordered in 2006). Here's the GSK press release. The total price of this new order is $97 million.

A few weeks later, GSK announced an agreement with the United Kingdom to deliver its vaccine "as soon as possible after a pandemic outbreak has been declared." Here's that announcement and coverage of both items from CIDRAP News.

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Unrelated to the GSK developments was news from NIH of research that could reduce the 6 month or longer delay between the start of a pandemic and the arrival of a specific vaccine against it. In the journal Science, Dr. Gary Nabel and colleagues report (free abstract) on a technique that could develop predicted variants of avian influenza before such mutations occur naturally, in effect giving vaccine development a head-start.

The background, methods, and possible implications of the research are all summarized nicely in this NIH announcement -- "NIH Scientists Target Future Pandemic Strains of H5N1 Avian Influenza." Here's coverage of the same news from Reuters, with a slightly bolder headline -- "New bird flu vaccine may prevent outbreak."

From Pediatrics: GSK rotavirus trials; trial of school-based flu vaccine program

In a slow midsummer period for vaccine news, two papers appearing in the journal Pediatrics this month deserve mention:

• "Dose Response and Efficacy of a Live, Attenuated Human Rotavirus Vaccine in Mexican Infants" -- This is a report on a trial of GSK's rotavirus vaccine, Rotarix. The study of 405 infants showed the vaccine to be safe and effective. Rotarix is still awaiting U.S. licensure -- the application was filed late last month, according to this announcement -- but it is already available around the world (including the EU, as this 2006 press release announced). With Merck's rotavirus vaccine, RotaTeq, available in the U.S. since 2006, another Merck-GSK head-to-head showdown is bound to occur, albeit one certain to be far less noticeable than the imminent competition for the HPV vaccine market likely to begin in 2008.

• "Mass Distribution of Free, Intranasally Administered Influenza Vaccine in a Public School System" -- The paper reports on a school-based influenza vaccination program in the Knoxville, TN area. Roughly 24,000 of 53,000 students received the FluMist vaccine, an encouraging number according to the study's authors. Of concern, however, was the amount of resources (notably, 6900 person-hours of labor) needed to execute the program. The program described here was funded in part by MedImmune (since purchased by AstraZeneca), the manufacturer of FluMist. Nevertheless, the paper's authors are correct to note the value of trials such as this in evaluating the feasibility of school-based programs to increase pediatric vaccination rates or as part of pandemic response efforts.
  

GSK gives to WHO bird flu vaccine stockpile; cell-based seasonal flu vaccine approved in EU

Some influenza-related goings-on this week:

• Yesterday, GSK announced via press release its plan to donate to WHO 50 million doses of its pre-pandemic avian influenza vaccine. WHO responded with a press release of its own, noting some of the many, many still-to-be-answered questions regarding if, when, and how such a stockpile would be used. Here's the AP story on the announcement. While a nice corporate gesture, vaccine doses for 25 million people -- delivered over 3 years, no less -- seems like a drop-in-the-bucket in the event that anything even resembling the estimates of policy-makers comes to fruition. Also, we've discussed the many uncertainties regarding the value of pre-pandemic vaccines previously, but suffice it to say, the benefit of such vaccines is uncertain today, much less three years from now in light of the viral mutation that would precede a pandemic in humans. All that said, this news can be seen as a good start, one could say, but by no means a major step in preparedness.

• In seasonal flu news, the EU approved a cell-based vaccine by Novartis, likely to be the first marketed flu vaccine produced without the use of eggs. Here's the AP story, courtesy of the Washington Post, and the Novartis press release. The story notes that the vaccine will not be available throughout the EU until the 2008-09 flu season and that U.S. approval will be sought next year. In light of the well-rehearsed problems with egg-based flu vaccine production (most notably the 2004 shortage), this may prove to be a major moment in flu vaccine development.

More Benefits of Gardasil?

With GSK's HPV vaccine -- Cervarix -- about to enter the final stages of FDA review prior to its all but certain licensure in the coming months, the marketing battle between GSK and Merck is about to begin in earnest.

One precursor of what's to come has been the occasional announcements and published papers noting protection against additional HPV strains beyond those specifically included in the vaccine. We've linked to many of those items previously.

Another sign is this headline: "Gardasil Guards Against Vaginal, Vulval Cancers: Researchers found cervical cancer vaccine reduced risk of lesions by 49%". The story is based on a paper in the latest issue of The Lancet by Joura and colleagues (abstract available here with free registration).

GSK planning head-to-head comparison of HPV vaccines

Earlier this month, GSK announced its plans to conduct a head-to-head clinical trial comparing its HPV vaccine, the still-unlicensed Cervarix, with Merck's Gardasil. Here's the GSK press release and a provocatively-headlined story from the Philadelphia Inquirer, "Area drug firms go to war over vaccine."

As the story notes, such a trial design is rare in medicine and all but unheard of for a vaccine. There's little doubt that this move by GSK is an attempt to frame an argument for the superiority of its HPV vaccine, despite the numerous advantages of Merck's Gardasil at present, among them, an increasingly longer head start in the market, immense media coverage over the past year, data showing 100% effectiveness (with respect to the HPV strains included in the vaccine), and the additional protection it provides against genital warts. Whatever their motives, head-to-head comparisons are helpful to patients and physicians, and it would by no means be a bad thing for other manufacturers of pharmaceuticals and vaccines alike to follow this lead, despite the high risks.

A sidebar piece in the same issue of the Inquirer looked at cost and access issues related to Gardasil. One interesting item: According to Merck's Richard Haupt, about $80 million worth of Gardasil had been sold through October, which he describes as "an extraordinary uptake." At Merck's listed price of $120/dose, that works out to roughly 660,000 doses, or enough to fully vaccinate 220,000 girls and women. (That number is likely higher, given the discounts offered to government programs and other groups).

Potency concerns for pandemic flu vaccine stockpiles; HHS planning update; more contracts awarded

For months, we've been discussing some of the many challenges and potential problems associated with the "pre-pandemic" avian flu vaccines currently being developed, tested, and stockpiled. More reason for concern came late last week, when this CIDRAP News story reported that a significant percentage of the stockpile has lost potency, resulting in a one-million-person decrease in the number of people who could potentially be protected by vaccine doses currently on hand (3 million, down from 4 million in an HHS document released in July). Here's an excerpt from the story, quoting an HHS spokesman:

"'All vaccines have shelf lives,' Hall told CIDRAP News. 'The early vaccine that was purchased, the first lots, have begun to lose their potency.'

He said the potency has begun to decrease for 'the majority' of doses in the stockpile, adding, 'That doesn't mean it goes from 100 percent to zero percent' or that the doses would be unusable."

On Friday, a day after the story above appeared, the same HHS spokesman seemed to walk back his earlier comments in this CIDRAP follow-up, explaining that only 20% of the current doses on hand are losing potency, not "a majority," as he previously said. Either way, it should come as a surprise to no one that these vaccines have a limited shelf life, an issue avoided by seasonal flu vaccines on account of their annual reformulations. Even with full potency, the vaccine doses in question are from "clade 1" virus samples from 2004. Since early this year, vaccine development has been based on a 2005 sample, working toward "clade 2" vaccines expected to be a closer fit to a possible pandemic strain.

All of this news came as a result of the release last week of the latest HHS Pandemic Planning Update. Not a lot of news in the 13-page report (and, thus, virtually no news coverage about its release), but it provides a good overview of the current status of U.S. planning and spending.

Finally, HHS announced today that another $200 million in contracts have been awarded to Sanofi Pasteur, Novartis, and GlaxoSmithKline for an additional 5.3 million doses of "clade 2" pre-pandemic vaccines, enough to vaccinate roughly 2.7 million people. (Here's the story from Reuters.) This would double the current stockpile (notwithstanding further decreases in potency of older vaccines), but still represent only a bit more than 1/4 of the goal of having enough vaccine stockpiled for 20 million Americans.

Fifth vaccine approved for upcoming flu season

Yesterday, the FDA approved FluLaval, a seasonal flu vaccine developed by ID Biomedical, a subsidiary of GSK. Here are the FDA press release and news items from Time and CIDRAP News.

FluLaval joins the four vaccines approved by the FDA in early August for the upcoming flu season, as we wrote about here. It's an injected vaccine (like three of the other four -- the exception being the nasally-administered FluMist) and is licensed for use in adults 18 and older. Among the five products, this year's supply is expected to set a record, with estimates of 115 doses being available in the U.S. Today's New York Times has a related story about the surge in flu vaccine supply.

The challenge for health care providers and public health officials will be to see that most or all of these doses are administered to patients, as the current record for vaccinations in a single flu season is 83 million, as we wrote last month. However, compared to the much-publicized shortages of years past, this is a far better 'problem' to face.

FDA approves 2006-2007 flu vaccines

News from Washington yesterday that the FDA approved the vaccines to be used for the upcoming flu season. Here's the FDA press release and AP story regarding the announcement.

These approvals are an annual occurrence, as manufacturers produce flu vaccines including the specific strains of the virus recommended by WHO and FDA. There are four vaccines available:

• Fluvirin (Novartis Vaccines, formerly Chiron)
• Fluarix (GSK)
• Fluzone (Sanofi Pasteur)
• FluMist (Medimmune)

FluMist is the increasingly popular nasally-administered vaccine, the other three are injected (and few patients know which of the three they receive). In total, the FDA estimates a supply of approximately 100 million doses in the U.S. for the season.

Good news for GSK bird flu vaccine development

We'd be remiss not to at least mention the headlines generated regarding GSK's avian flu vaccine. In short, they announced that their candidate vaccine provided significant levels of antibody protection in more research subjects at a much lower dose than another vaccine in development (namely, the Sanofi vaccine which we wrote about here back in March.)

Here's a sampling of the coverage: New York Times, Washington Post, Philadelphia Inquirer, and Associated Press.

This may prove to be excellent news for pandemic preparedness efforts, but as many of the quotes in the stories above illustrate, it's wise to be cautious for now while estimating the significance of the announcement. Part of the reason for this is that the GSK data has not yet been published in the medical literature -- we're all relying on press releases (such as this one) and media briefings at the moment.

More generally, there are a number of issues arising from any 'pre-pandemic' vaccine (i.e., one developed before the virus mutates into a form that spreads easily from human-to-human.). We've written about many of these in the past in response to prior developments, but the editors at Effect Measure explain in this post a number of the unanswered questions specifically relating to the GSK announcement. They consistently do an excellent job covering all aspects of avian flu (not just vaccines) and public health in general, and this post is no exception.

More on HPV vaccine criticisms, collaboration, and competition

As predicted, a slew of stories are appearing about HPV vaccines, with Gardasil's expected licensure later this week. A sampling of the best:

• Merck's $4 billion PR problem (Fortune) -- A look ahead at the (possible) battles that await Gardasil, particularly regarding opposition to state mandates. Includes quotes from Barbara Loe Fisher, perhaps the most prominent critic of vaccines, vaccine safety, and U.S. vaccination regulation and policy.

• Vaccine helps show value of partnerships (Boston Globe) -- Examines the collaboration between researchers at the National Cancer Institute, particularly Dr. Douglas Lowy, and subsequent commercial partners Merck and GSK in bringing HPV vaccines from the earliest stages of research through licensure. A great example of a successful public-private partnership, but one all but certain to add to the uneasiness of those who think the relationship between government and the pharmaceutical industry are too cozy.

• Cancer vaccine shows promise for older women (Reuters) -- Realizing the massive attention Merck's Gardasil will receive this month while its vaccine is months behind, GSK chose a conference this weekend to release new trial data on Cervarix. A 666-subject study of women age 15-55 showed that the vaccine generated antibody levels equal to those seen in younger women in earlier trials. What isn't answered in this or other stories is how beneficial it would be to launch HPV vaccination campaigns for older women, as many will have already been infected with the HPV types included in the vaccine.
  

Pharma sparring over which HPV vaccine is better

Aside from the controversy that likely will shadow HPV vaccines' introduction, Merck and GSK are fully engaged in a not-so-friendly debate over whose vaccine is superior. Those in attendance at the last ACIP meeting in February caught a glimpse of this jockeying, and a piece in today's Philadelphia Inquirer covers the latest round of salvos.

First, the news. A paper was published today on the website of The Lancet (subscription required) reporting new trial data of the GSK vaccine, Cervarix. It is titled "Sustained efficacy up to 4·5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial." Here's the GSK press release.

Two newsworthy items: (1) The follow-up study showed 100% efficacy over 4.5 years against the precancerous lesions caused by HPV. The data was gathered from a sample of 776 women who participated in an earlier vaccine trial, according to Forbes. For both vaccines, long-term efficacy data is not yet available, so it's unclear whether booster doses may be needed. 4.5 years of protection is a start, but ultimately, life-long protection is necessary.

(2) The paper also suggests broader protection against more subtypes of HPV than the two specifically included in the vaccine. From the press release:

"The study provided evidence that GSK’s candidate vaccine demonstrated substantial protection against infection with the third and fourth most prevalent cancer-causing types of HPV, namely types 45 and 31. This protection also extends over 4.5 years. GSK is conducting further large studies to determine the potential mechanism and extent of the demonstrated broader oncogenic protection."

If this finding holds up, it would mean that GSK's vaccine provides protection against up to 80% of cervical cancers in the U.S. (up from the 70% figure originally believed).

As the Inquirer reports, Merck scientists were skeptical of the GSK announcement:

"Merck...immediately questioned GlaxoSmithKline's study. One of its HPV researchers, Eliav Barr, called Dubin's analysis 'unorthodox' and emphasized that Merck also was testing for additional virus protections. Merck's vaccine already has been shown to help prevent HPV infections that cause genital warts.

Reacting to Merck's criticism, Dubin defended the study results as highly reliable and suggested that a reporter 'ignore' Merck's comment."

We've discussed the differences between each company's HPV vaccine and other recent developments previously (here, here, here, and here). While Merck's inclusion of additional HPV subtypes responsible for genital warts in their vaccine gave it the early competitive advantage (as males could also benefit from it), today's news signals that the battle for superiority is far from over.

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.

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.

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.

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.