Worrisome Infection Eludes a Leading Children’s Vaccine
By LAURA BEIL
Published: October 13, 2008
A highly drug-resistant germ has become a common cause of meningitis, pneumonia and other life-threatening conditions in young children. The culprit ― a strain of strep bacteria ― can conquer almost all antibiotics in pediatrics, and has dodged a vaccine otherwise credited with causing the number of serious infections in children to plummet.
Since 2000, American toddlers have been immunized against Streptococcus pneumoniae, or pneumococcus, an organism that preys largely on children younger than 5 and the elderly. Pneumococcal meningitis can be fatal, and survivors are often left with deafness and other lifelong neurological problems.
And by most measures, the vaccine has worked: by 2002, rates of infection from these bacteria had dropped as much as 80 percent in some places. But progress has now stalled, and infection with a particular type of pneumococcus, Serotype 19A, is steadily rising.
“It’s very much a concern,” said Bernard Beall, a pneumococcal expert at the federal Centers for Disease Control and Prevention. Last year, in The Journal of the American Medical Association, pediatricians described an outbreak of Serotype 19A ear infections in Rochester that could be cured only by surgically implanting tubes, or by turning to adult medicines not yet tested for safety in children.
A greater worry, however, is the frequency of meningitis, pneumonia and bloodstream infections from Serotype 19A. Since 2001, rates of these and other invasive pneumococcal diseases have crept upward, to more than 10 per 100,000 children from about 2 per 100,000. A fourfold increase in life-threatening infections has also occurred among the elderly.
The vaccine, Prevnar, is aimed at seven types of bacteria that were responsible for 70 to 80 percent of pneumococcal illness during the 1990s. Because pneumococci come in 91 forms, experts have worried from the start whether bacteria that were just as deadly, but not wiped out by the vaccine, might move in as opportunists when the competition suddenly vanished.
“Nature abhors a vacuum,” said Dr. Steven Black of Cincinnati Children’s Hospital. Indeed, almost all pneumococcal infections among American children today are caused by versions not covered by the vaccine, and 19A is leading the way. “People hoped against hope it wouldn’t happen,” he said.
The vaccine’s manufacturer, Wyeth, says it has been working quickly to develop a new product to counter 19A and five other pneumococcal variations, along with the original seven. The company will release results of the first large studies of the newer version this month at an infectious disease meeting in Washington.
“There was no point where we said to ourselves, ‘We missed it, we need to put in 19A,’ ” said Emilio A. Emini, head of vaccine research and development for Wyeth. The company was always prepared to remake the product, he said.
Once a new vaccine demonstrates that it can protect against pneumococcus, it must work its way through the approval process ― passing tests of effectiveness and safety ― before it can be licensed. Researchers will also try to determine whether young children who have been immunized with the old Prevnar should be revaccinated to protect themselves from 19A.
The remodeling of a vaccine so soon after its approval is highly unusual, but so was the effort to tackle pneumococcus.
The bacteria live in the nose and throat, usually as microbial freeloaders of no consequence. Occasionally ― often after a simple viral infection ― pneumococci slip into inner areas of the body and cause disease. Weaker immune systems in the very young and the very old leave them most vulnerable. (The pneumonia shot in older people includes 19A, but many elderly people have not received the immunization.)
Not all of the 91 incarnations of pneumococcal bacteria are dangerous. They developed so much variety by mingling in the back of the throat, exchanging genetic material as eagerly as children trading Halloween candy. The variation in genes slightly alters how the bacteria function and how they are received by the immune system.
For vaccine manufacturers, pneumococci’s diversity presented a challenge: how to teach the immune system to recognize a target that may look a little different from child to child. “This is the most complex biological product ever made,” Dr. Emini said.
Serotype 19A was around in the 1990s, though uncommon, and the vaccine includes a similar version called 19F. The hope in 2000 was that 19F looked enough like 19A to set off an immune reaction. It did not.
Experts say it is hard to know what role the introduction of Prevnar may have played in the rise of the bacteria, which was gaining momentum in some countries before the vaccine’s adoption. For example, researchers from GlaxoSmithKline, which is introducing its own pneumococcal vaccine, reported last month that Serotype 19A became more common in Belgium from 2001 to 2004 ― years when pneumococcal vaccination was rare in that country. Similar reports have emerged from China, South Korea and Israel.
Pneumococci ebb and flow in natural cycles, and some types have gained a survival advantage by growing resistant to a host of drugs. The vaccine may have simply amplified natural trends..
“I don’t think anyone can tell you the relative contributions of these factors,” said Dr. Sheldon L. Kaplan of Texas Children’s Hospital in Houston. This summer, he and his colleagues described a growing number of cases of drug-resistant mastoiditis, an infection of an inner-ear bone, from 19A.
Experts are now watching to see how forcefully the organism will spread before the new immunization arrives. Wyeth says it hopes to file an application with the Food and Drug Administration in 2009.
Disease experts also wonder what organisms like 19A mean for the future of pneumococcal infections. Public health experts once hoped the infection could be defeated, but it now appears that pneumococci may be playing a game of cat and mouse.
“The pneumococcus has shown an extraordinary ability to evolve to our strategies,” said Dr. Beall of the C.D.C.
Yet he and others are quick to say that immunization remains highly effective, even if it leaves some children behind. “This is not a failure of the vaccine,” said Dr. George H. McCracken Jr. of the University of Texas Southwestern Medical Center at Dallas. Even with the rise of 19A, children are much less likely to become ill from pneumococcal infections.
Dr. McCracken hopes that researchers will one day avoid threats like 19A entirely by developing a vaccine that primes the immune system to recognize some element common to all 91 types of pneumococci ― in the way a quiche, an omelet and a custard pie are all versions of eggs. But until such an immunization comes along, he said, pediatricians will be forced to battle the pneumococcus as they always have, by trying to stay one strain ahead of its game.
Vol. 298 No. 15, October 17, 2007 JAMA
Emergence of a Multiresistant Serotype 19A Pneumococcal Strain Not Included in the 7-Valent Conjugate Vaccine as an Otopathogen in Children
Michael E. Pichichero, MD; Janet R. Casey, MD
Context Concern has been raised about the possible emergence of a bacterial strain that is untreatable by US Food and Drug Administration (FDA)–approved antibiotics and that causes acute otitis media (AOM) in children.
Objective To monitor continuing shifts in the strains of Streptococcus pneumoniae that cause AOM, with particular attention to capsular serotypes and antibiotic susceptibility, following the introduction of a pneumococcal 7-valent conjugate vaccine (PCV7).
Design, Setting, and Patients Prospective cohort study using tympanocentesis to identify S pneumoniae strains that caused AOM in children receiving PCV7 between September 2003 and June 2006. All children were from a Rochester, New York, pediatric practice.
Main Outcome Measure Determination of serotypes and antibiotic susceptibility of S pneumoniae causing AOM.
Results Among 1816 children in whom AOM was diagnosed, tympanocentesis was performed in 212, yielding 59 cases of S pneumoniae infection. One strain of S pneumoniae belonging to serotype 19A was a new genotype and was resistant to all antibiotics approved by the FDA for use in children with AOM. This strain was identified in 9 cases (2 in 2003-2004, 2 in 2004-2005, and 5 in 2005-2006). Four children infected with this strain had been unsuccessfully treated with 2 or more antibiotics, including high-dose amoxicillin or amoxicillin-clavulanate and 3 injections of ceftriaxone; 3 had recurrent AOM; and for 2 others, the infection was their first in life. The first 4 cases required tympanostomy tube insertion after additional unsuccessful antibiotic therapies. Levofloxacin was used in the subsequent 5 cases, with resolution of infection without surgery.
Conclusion In the years following introduction of PCV7, a strain of S pneumoniae has emerged in the United States as an otopathogen that is resistant to all FDA-approved antibiotics for treatment of AOM in children.
Author Affiliations: University of Rochester and Legacy Pediatrics, Rochester, New York.
Emergence of Antimicrobial-Resistant Serotype 19A Streptococcus pneumoniae―Massachusetts, 2001-2006
Streptococcus pneumoniae (pneumococcus) is a leading cause of otitis, sinusitis, pneumonia, and meningitis worldwide. Treatment of the most serious type of pneumococcal infection, invasive pneumococcal disease (IPD),* is complicated by antimicrobial resistance. Widespread introduction in 2000 of heptavalent pneumococcal conjugate vaccine (PCV7) against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F resulted in a decline in antimicrobial-nonsusceptible IPD in the United States1-2, including in Massachusetts.3 However, development of antimicrobial resistance in serotypes not covered by PCV7 is a growing concern1, 4. In Massachusetts during 2001-2006, IPD surveillance identified an increased number of cases in children caused by pneumococcal serotypes (most notably 19A) not covered by PCV7 and an associated increase in antimicrobial resistance among these isolates. This report examines these trends and clinical characteristics of Massachusetts patients with antimicrobial-nonsusceptible, non–PCV7-type IPD. The findings indicated that, despite increases in incidence of antimicrobial-nonsusceptible . . .
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