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By Julie Steenhuysen
CHICAGO, May 23 (Reuters) - Kathrin Jansen is amicrobiologist with at least two breakthrough vaccines to hername: she brought the cervical cancer vaccine Gardasil to marketfor Merck and helped develop the $4 billion a year pneumonia andmeningitis vaccine Prevnar 13 for Pfizer.
Jansen's next vaccine success could come by taming thesuperbug MRSA, a drug-resistant bacterium that she has seenravage a healthy man up close and personally.
Methicillin-resistant Staphylococcus aureus infects anestimated 53 million people globally and costs more than $20billion a year to treat. In the United States alone, MRSA kills20,000 Americans each year, exceeding annual deaths from AIDS.
Jansen watched the infection unfold two years ago whenvisiting her stepfather, who was in the hospital for a hipreplacement. The man in the bed next door died soon after MRSAattacked the vascular graft in his leg.
"He went in healthy and died very quickly," recalls Jansen, senior vice president of vaccine research and early developmentat Pfizer Inc, the world's largest drug maker. She saysthe experience steeled her resolve to develop an effectivevaccine that could prevent such deaths.
But Staphylococcus aureus has proven a tenacious adversary.In the past decade, vaccine candidates by NabiBiopharmaceuticals and Merck & Co Inc failed in costly,late-stage clinical trials. Now, led by Jansen, Pfizer is takinga shot. Competitors, including vaccine giants GlaxoSmithKline, Novartis and Sanofi, are, too.
And while the race could lead to a viable vaccine,potentially worth billions in sales, critics say companies maybe risking costly failure with so much work on a bacterium thatis still barely understood.
'BAG OF TROUBLE'
Staph has been living in and on its human hosts forcenturies. At any given time, 25 to 35 percent of individualswill test positive for staph, often with no symptoms. But thebacterium can cause a range of diseases from boils and impetigoto raging blood infections and deadly bacterial pneumonia.
The discovery of penicillin in 1928 gave doctors a way todefeat staph infections, but overuse and misuse gave rise todrug-resistant staph. Methicillin was developed to overcome drug-resistance, but by the 1960s, staph evolved new defenses toovercome this more powerful version of penicillin.
Thus began the decades-long battle againstmethicillin-resistant staph, now the most common cause ofhospital-acquired infections that is increasingly spreading intoarmy barracks, prisons and daycare centers.
Dr. Bill Gruber, a Pfizer senior vice president who ledclinical trials for Prevnar 13 and is running the company'sStaph aureus trials, thinks of the bacterium as "a little bag oftrouble."
"Basically, it has a number of different toxins and defensesto try to defeat you."
That may explain why vaccines from Nabi and Merck failed.Both tried to defeat this bug by attacking on just one front.
The vaccine by Nabi, now Biota Pharmaceuticals,focused only on the sugar capsule the bacteria make to hide fromthe immune system, while Merck's focused on a single proteinthat helps staph gets its nutrition. Neither lived up toexpectations.
"We've learned that just focusing on one target of Staphaureus might not be sufficient," said Dr. Buddy Creech, aninfectious diseases expert at Vanderbilt University.
IT TAKES STAMINA
Jansen has been working on a Staph aureus vaccine for thepast decade, first at Merck, then at Wyeth, and now at Pfizer.
The East German-born scientist - who fled to the West in1960 and earned her PhD in biology at Philipps University inMarburg - says it takes stamina to develop a successful vaccine,a process that can take 15 years or more. With the cervicalcancer vaccine Gardasil, which had 2012 sales of $1.6 billion,it took 14 years from lab bench to government approval. "That'sactually a fast development program," she said.
With Staph aureus, it took eight years from the firstexperiments to human safety trials. Now, it could take anotherseven to 10 years to wind up clinical trials, putting the teamabout midway through the process.
Pfizer's initial vaccine targeted three mechanisms key tostaph's survival and ability to cause disease. Two of thosefocused on sugar capsules. The third attacks a mechanism called"clumping factor," which allows bacteria to stick to proteinswhen they enter the body.
But Jansen's team wanted one more point of attack. Theyadded a fourth antigen, a protein that allows the bacterium tosteal manganese - a key nutrient - from host cells.
The result is a four-antigen vaccine that generates antibodyresponses at distinct points of the life cycle of the bug. Thecompany is testing this in Phase 1/Phase 2 trials in healthyadults in the United States.
If Pfizer gets the results they hope for, likely later thisyear, the company expects to meet with regulators to iron out aplan for larger trials involving thousands of individuals.
Initially, the vaccine would be aimed at preventinginfections in millions of people globally who need electiveprocedures such as a hip replacement. Ultimately, it could beused to protect people at risk in the broader community.
RIVAL VACCINES
Pfizer is furthest along, but the large, untapped market,estimated to be worth $3 billion to $4 billion a year, has drawninterest from several companies.
GlaxoSmithKline has been quiet about its approach. Thedrugmaker had been partnering with Nabi's failed StaphVaxcandidate, and in 2009 bought another Nabi candidate calledPentaStaph for $46 million.
Company researchers declined to discuss their program, butGlaxo spokeswoman Melinda Stubbee confirmed the company has afour-component vaccine in Phase 1 development. "We are stillevaluating the data and haven't yet announced plans to presentthe data or to pursue further development," she said.
NovaDigm Therapeutics, a private company based in GrandForks, North Dakota, is developing a single-antigen vaccine thattargets both staph and yeast infections caused by the fungusCandida.
Other rivals with early-stage programs include Novartis,which has a vaccine in Phase 1 trials, and Sanofi, which ispartnering with privately held biotech Syntiron.
Although academic researchers applaud these efforts, theysay companies may be rushing into trials too soon, especiallywhen so much is unknown about how staph interacts with people.
"Our development of Staphylococcal vaccines has predated anadequate understanding of the human response to infection,"Creech said.
For instance, it is still not clear whether a Staph aureusvaccine that protects against skin infections will also protectindividuals from bloodstream infections. It may be that insteadof preventing infection, some vaccines will merely bluntinfection.
Dr. Robert Daum, who leads the MRSA Research Center at theUniversity of Chicago Medical Center, doubts any of the currentcandidates will make it into widespread use. "I am convinced weneed a vaccine. I'm just not sure anyone knows how to make oneyet."
Jansen, who knows Daum, said she understands his skepticism."I'm a microbiologist. I know bacteria pretty well. They arevery potent adversaries."
She says there's a reason the company was not the first outof the gate. "We wanted to make sure that we looked under allthe rocks and found what we needed to find."
Tests in animals and people suggest the vaccine inducesproduction of antibodies that defeat staph's defenses and killthe bacteria. "To our knowledge, we are the only ones who havedemonstrated very, very robust killing responses."
That was enough for Jansen. "We essentially said, 'That'sit. We put it together as best as we know how. Now is the timeto test it.'"
