Impressive data on likely RotaTeq impact; Rotarix ACIP recommendation added

A good amount of news about rotavirus vaccination in the U.S. came out of Atlanta yesterday. First, a CDC report issued as an MMWR Early Release detailed encouraging data on trends regarding the impact of rotavirus. Titled "Delayed onset and diminished magnitude of rotavirus activity -- United States, November 2007-May 2008," the report examines data from clinical laboratories as to the frequency and timing of confirmed rotavirus samples during the rotavirus season currently underway.

In addition to seeing a delay of 2-4 months in the start of this year's rotavirus season, the report states that the number of positive tests for rotavirus was "substantially lower during the 2007-08 rotavirus season than during any of the prevaccine seasons." These trends coincide with increasing use of RotaTeq, Merck's rotavirus vaccine, approved in 2006. (Despite being the most likely explanation, both the report and an accompanying CDC press release acknowledge that the role of the vaccine cannot be stated definitively from these data alone.)

If these changes are, in fact, attributable to RotaTeq, there are also early signs that the benefit of vaccination may extend beyond those vaccinated to the community-at-large. The MMWR piece explains:

"Because the changes in rotavirus activity appear more pronounced than might be attributed to direct protective effects of vaccination alone, the results of this analysis suggest that vaccination of a proportion of the population might offer indirect benefits to unvaccinated children (i.e., herd immunity) by reducing transmission of rotavirus in the community. "

Needless to say, more data will be needed to see whether this positive trend continues in future years, as well as whether the declines in positive tests for rotavirus correspond with decreases in rotavirus-induced hospitalizations and deaths as vaccination programs proceed.

Here's coverage from the Los Angeles Times and the Washington Post, and a press release by Merck touting the positive news.

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In other rotavirus vaccine news, GSK's Rotarix, approved by FDA in April (as we noted previously), was added yesterday by the Advisory Committee on Immunization Practices to its universal recommendation for infants. No preference was stated between the two vaccines by ACIP. Here's a story on the recommendation (technically not official until published in MMWR) by the Associated Press.

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Unrelated to rotavirus, the ACIP also voted to add recommendations for two combination vaccines as options for parents and physicians: Sanofi Aventis' Pentacel (DTaP, polio, Hib) and GSK's Kinrix (DTap, polio), both of which would reduce the total number of injections needed to complete the recommended vaccination series. This Reuters story has more.

No evidence of RotaTeq-intussusception link observed

Students of contemporary vaccine history are likely familiar with the story of RotaShield, a vaccine against rotavirus licensed in 1998 but withdrawn a year later following the apparent correlation between it and intussusception, a potential life-threatening bowel obstruction.

The clinical testing of RotaTeq, the Merck vaccine licensed in 2006, showed no such link, yet alarms were raised by a 'public health notification' titled "Information on RotaTeq and Intussusception" issued by FDA in February 2007. Despite its title, the announcement did not suggest that intussusception rates among vaccinees were any greater than what could be expected in the general population.

This month's issue of Pediatrics examines the topic in much greater detail, in a paper from CDC and FDA researchers titled, "Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States, February 1, 2006, to September 25, 2007". Based primarily on VAERS reports, the study concludes that there is no association between RotaTeq and intussusception.

Information about general trends in intussusception rates -- independent of a connection to vaccines -- appeared in a paper in the May issue of Pediatrics: "Trends in Intussusception Hospitalizations Among US Infants, 1993–2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program".

Updates: HIV vaccine reassessment; 2nd rotavirus vaccine approved; Avian flu vaccine supply

Here are a few updates on topics we've been covering over the past several months:

• HIV vaccine research -- Several months after the failure of what was billed as the 'most promising' HIV vaccine candidate, NIAID organized a meeting late last month to reassess the state of HIV vaccine research and plans for the future. The "Summit on HIV Vaccine Research and Development" garnered significant media attention from the Washington Post and New York Times, among other outlets. The apparent take-away message from the meeting was that renewed effort must be directed toward basic research and novel ideas. A subsequent Times editorial argued that the potential benefit of a vaccine is too great to give up hope. A webcast of the meeting is available at the NIAID summit website.

• Rotavirus vaccines -- As expected, on Thursday, FDA approved GSK's Rotarix, now the second rotavirus vaccine available in the United States. Here's a story from the Associated Press, the FDA press release and the GSK release. The major difference between Rotarix and Merck's RotaTeq is that Rotarix requires two doses compared to three for RotaTeq. No word yet on the price of Rotarix, which had already been licensed in over 100 countries. It is expected to be available in the U.S. later this year.
  

• Pandemic flu planning -- Another update on the federal government's pandemic flu planning was released by HHS Secretary Michael Leavitt late last month. Updates on vaccine development and stockpiling figure prominently in the report. It notes that enough pre-pandemic vaccine for 13 million people was stockpiled by the end of 2007. This CIDRAP News story has more details.

FDA: GSK rotavirus vaccine appears safe and effective

Rotarix, the rotavirus vaccine developed by GSK, moved closer to U.S. licensure on Friday, as an FDA staff report stated that clinical trial results suggest that the vaccine is safe and effective.

Here is coverage of the news from The Wall Street Journal, Associated Press and Dow Jones. Rates of intussusception -- the gastrointestinal condition that doomed the first rotavirus vaccine, Rotashield, in 1999 -- were not significantly different in those receiving Rotarix versus control groups receiving a placebo.

A positive recommendation from government advisors at next week's meeting of FDA's Vaccines and Related Biological Products Advisory Committee would likely be the final step prior to licensure in the U.S. Rotarix is already approved in over 90 countries, according to GSK.

Merck's rotavirus vaccine, RotaTeq, was approved in February 2006 and is currently recommended for all infants at 2, 4, and 6 months of age

Gardasil, RotaTeq sales top Merck quarterly report

As we've written previously, corporate financial reports aren't exactly our forte. However, the price of Gardasil (and, to a lesser extent, RotaTeq) have been prominent in policy discussions both in the U.S. and internationally, so this week's sales news from Merck is worth noting here.

This Merck document includes a table listing sales for various vaccines in the third quarter of 2007. Among the highlights:

• Gardasil: $418 million in sales
  
• RotaTeq: $171 million in sales
  
• Zostavax: $61 million in sales
  
• All other vaccines: $593 million in sales
  

Remembering that these numbers represent only three months of sales, we can see clearly that the days in which vaccines were not thought of as potential profit centers for the pharmaceutical industry are long over. (Moreover, most European vaccine sales are not included in these figures, making the true totals even higher.)

Here's coverage from Reuters and the Associated Press, which reports that total Gardasil sales for the first 9 months of 2007 is $1.14 billion. Also of interest is the detailed news release from Merck. According to is, Gardasil has now been approved in 86 countries (with 50 more pending) and RotaTeq is approved in 69 countries.

There's no doubt that many hope that these remarkable sales figures is the U.S. and elsewhere will encourage Merck to expand its programs (like this one) to deliver free or low-cost vaccines to those parts of the world that would benefit most from them.

Merck report: $358m in Gardasil sales for Q2; $1 billion total for vaccines

While we don't typically highlight corporate earnings reports or similar news, the quarterly report released Monday by Merck for April-June 2007 provides some new information about the growing market for vaccines, and, in particular, Gardasil. Here's coverage from yesterday's New York Times, "Another Quarter of Strong Results by Merck," and a similar story from Reuters.

Since this news comes directly from the company, the Merck press release is particularly useful. Here's part of what it says about vaccines:

"Total vaccine sales, as recorded by Merck, were $1.0 billion for the quarter, compared to $349 million in the second quarter of 2006. The growth in vaccine sales was led by the performance of GARDASIL along with strong contributions from ROTATEQ and other pediatric vaccines. Vaccines in most major European markets are sold through the Company’s joint venture, Sanofi Pasteur MSD, and the results from its interest in the joint venture are recorded in equity income from affiliates.

Total sales as recorded by Merck for GARDASIL, the Company's cervical cancer vaccine, were $358 million for the second quarter. As of the second quarter, GARDASIL has been approved in 80 countries, many under fast-track or expedited review; and launched in 59 of those countries. The vaccine remains under review in approximately 40 other countries.

ROTATEQ, Merck's vaccine to help protect children against rotavirus gastroenteritis, achieved worldwide sales, as recorded by Merck, of $119 million for the quarter. As of the second quarter, ROTATEQ has been approved in 61 countries and it has launched in 22 of those countries."

The release goes on to note sales figures for Proquad ($89 million), Varivax ($147 million), and Zostavax ($47 million).

A companion document released by Merck breaks down sales between the U.S. market and internationally. Nearly 80% of Gardasil sales were in the U.S. ($286 million), as were an amazing 96% of RotaTeq sales ($114 million). There's little doubt from these data that the U.S. is leading the way in the uptake of these two fairly new vaccines, despite the far greater need for cervical cancer and rotavirus prevention internationally.

Overall, $1 billion in vaccine sales for a single company in a three-month period is perhaps the best evidence to date of the potential profitability of vaccines to an extent not previously seen. As for Gardasil, it is difficult to work backwards from the sales figures given ($358m) to ascertain the number of doses sold during the April-June period, since governments and insurance companies pay less than the well-known $120/dose 'sticker price'. This CDC price list shows a cost of $96.75/dose for Gardasil as part of the Vaccines for Children program. Using those figures as endpoints, a very rough estimate would suggest 3-4 million doses were sold, or enough doses to fully vaccinate slightly more than 1 million girls.

Given the size of the population for whom vaccination is recommended (all females 11-26), the potential growth of the Gardasil market is staggering, perhaps explaining, in part, the company's apparent enthusiasm to promote its vaccine in advance of the arrival of GSK's Cervarix.

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.
  

Info on Kawasaki disease added to RotaTeq label

A colleague from CDC alerted us to this announcement regarding a change to the label of RotaTeq, Merck's rotavirus vaccine recommended to all infants at 2, 4, and 6 months. Here's the first paragraph of the CDC statement:

"The Food and Drug Administration (FDA) approved today a revised label for RotaTeq, a rotavirus vaccine manufactured by Merck and Co., Inc., to include information on reports of Kawasaki disease occurring before and after the vaccine’s licensure in February 2006. FDA has not made any changes to its indications for use of RotaTeq nor has it issued new or revised warnings or precautions. Likewise, the Centers for Disease Control and Prevention (CDC) has not made any changes in its recommendations regarding the use of RotaTeq. Healthcare providers and parents should remain confident in using RotaTeq in infants."

Here's the FDA release and a related story from Reuters (the only media outlet to have reported on this item as of now.)

General info on Kawasaki disease can be found here and here. It's a rare and poorly understood inflammatory condition that affects 4,000 American children annually.

The "label" referred to in the announcements above is actually this document, an 11-page, single-spaced, data-laden product insert unlikely to top the reading lists of most parents (or pediatricians, for that matter).

The FDA statement notes, "The cases reported to date are not more frequent than what could be expected to occur by coincidence," a statement that could also describe its announcement in February regarding intussusception reports among recipients of RotaTeq.

Similar to that earlier occasion, this announcement was seemingly made so that providers and parents may be vigilant in looking for symptoms of Kawasaki disease, in case a connection to the vaccine does exist. However, calling attention to severe conditions for which no evidence suggests a vaccine link may create undue confusion and worry among parents still told to vaccinate their children with RotaTeq. Admittedly, it is a difficult balance that must be weighed by policy-makers, but one that merits further study.

Renewed attention to possible rotavirus vaccine link to intussusception

A fairly significant amount of alarm was raised by an FDA statement last week titled "Information on RotaTeq and Intussusception". The statement reports 28 cases of intussusception -- the significant intestinal complication that led to the removal of the first rotavirus vaccine, RotaShield, in 1998 -- in children following administration of RotaTeq.

But what may have seemed at first glance to be a major announcement about the vaccine's safety was clarified later in the statement...

"Intussusception can occur spontaneously in the absence of vaccination. Of the reported 28 cases of intussusception, the number that may have been caused by the vaccine, or occurred by coincidence, is unknown."

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"The number of intussusception cases reported to date after RotaTeq administration does not exceed the number expected based on background rates of 18-43 per 100,000 per year for an unvaccinated population of children ages 6 to 35 weeks (CDC, unpublished data)."

In other words, there's no reason to be alarmed about the number of cases reported to date, but the statement, not unsurprisingly, did just that. This AP story by Andrew Bridges originally did not include any information about the background rate, likely contributing to the Alliance for Human Research Protection (and others, no doubt) misinterpreting the FDA item. "Merck rotavirus vaccine linked to 28 reports of life-threatening effect," is how the AHRP item describes the announcement, not at all what the FDA said.

CDC promptly released a statement attempting to clear up confusion. Among the 'key facts' they list:

• "We are not surprised by the number of reported intussusception cases following RotaTeq vaccination."
• "Intussusception, a form of bowel obstruction, occurs spontaneously in the absence of vaccination."
  
• "This notice does not mean there is a problem with the RotaTeq vaccine."

There's been no detectable coverage of this topic in the media since the initial FDA statement last week. It will, however, be discussed at this week's meeting of the ACIP, the agenda for which can be viewed here.

Assessing pediatrician attitudes on rotavirus vaccine

The January issue of Pediatrics has a number of items discussing RotaTeq, Merck's rotavirus vaccine. Most interesting to this group is a paper titled "Will pediatricians adopt the new rotavirus vaccine?," a survey of attitudes among 431 physicians (free abstract, subscription required for full text). Much of the data was presented at the February 2006 ACIP meeting at which RotaTeq received a universal recommendation.

Here's a portion of the results section:

"Of the respondents, 52% strongly agreed and 37% somewhat agreed with the need for a rotavirus vaccine. If recommended for routine use, 50% would strongly recommend and 34% would recommend but not strongly; 52% would begin to use within 6 months and 27% from 6 months to 1 year. The top 3 "definite" barriers to implementation included concerns about uniform coverage of vaccine by insurers, lack of adequate reimbursement, and parental reluctance because of withdrawal of previous rotavirus vaccine."

Rotavirus inventors to receive CHOP gold medal

As this front-page story in today's Philadelphia Inquirer reports, the three researchers responsible for the discovery of what ultimately became Merck's new rotavirus vaccine, RotaTeq, will receive the "Gold Medal" from the Children's Hospital of Philadelphia. As even the brief outline in the Inquirer story suggests, the story of RotaTeq could be a case study for the difficulties of developing new vaccines -- the work leading to this year's FDA licensure and ACIP recommendation extends all the way back to research conducted in 1980.

Congratulations to Paul Offit, Stanley Plotkin, and Fred Clark on this latest honor. (For the record, Offit and Plotkin are friends and colleagues who have contributed their insights and expertise in various ways to the development of the Ethics of Vaccines Project.)

Rotavirus vaccine recommendations published in MMWR

Back in February, the ACIP recommended Merck's rotavirus vaccine, RotaTeq, for universal administration to infants. While provisional recommendations were posted on the ACIP's website in May (as we discussed here), just yesterday did the recommendations become official upon their publication in MMWR. Here are the full recommendations.

The publication means a few things: 1) The process of insurance companies adding RotaTeq to their list of covered vaccines will likely accelerate over the coming months, and 2) professional groups and individual pediatricians will increasingly recommend vaccination to parents as it becomes a standard part of pediatric care.

Provisional rotavirus recommendations expected within a month

This afternoon, the National Immunization Program hosted a live netconference titled "Current Issues in Immunization". Among the topics covered in the one-hour session were revisions to the General Recommendations on Immunization, the document updated every few years that provides general guidance of immunization practices in the U.S. The revisions, addressing particulars of simultaneous administration of multiple vaccines and the impact of altered immunocompetence on vaccination recommendations, were discussed in detail at the February ACIP meeting.

Also presented was an update on the recently licensed and recommended rotavirus vaccine, Merck's RotaTeq. CDC's Dr. Umesh Parashar gave an overview of rotavirus epidemiology worldwide and in the U.S., contrasted RotaTeq with RotaShield (Wyeth's failed vaccine of 1998-99), and offered an update on the current status of the ACIP recommendation approved in February that all infants receive the vaccine at 2, 4, and 6 months.

According to Dr. Parashar, the ACIP recommendation is currently undergoing final clearance from the CDC and HHS. These required approvals are expected within the next month, at which point provisional recommendations will be posted online here. Recommendations do not become official until printed in the Morbidity and Mortality Weekly Report (MMWR), a step expected to occur sometime in fall 2006.

Still, federal government vaccination recommendations remain only recommendations unless individual states act to require the vaccine as a condition of school or day care attendance. These mandates are widely expected for RotaTeq, but require actions by state departments of health or (in some cases) legislatures. Mandates for rotavirus vaccination are not expected to be nearly as contentious as those for HPV vaccines in the months and years ahead.

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.