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PRIORITY PRESS - 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Vienna, Austria / April 10-13, 2010

According to the World Health Organization, Streptococcus pneumoniae is the leading cause of vaccine-preventable disease worldwide with more than 500,000 children <5 years of age estimated to die each year from pneumococcal infection. Life-threatening infections caused by this pathogen include pneumonia, meningitis and sepsis. In addition, conditions such as acute otitis media and sinusitis represent important health problems. Antibiotic use to treat these infections has contributed to the emergence of antibiotic resistance. “We really have very few solutions in the face of emerging resistance,” commented Dr. Christoph Wenisch, Kaiser Franz-Josef Hospital, Vienna, Austria, here at ECCMID.

Pneumococcal Vaccine Experience

The 7-valent pneumococcal vaccine (PCV7) covers a small percentage of the 93 known serotypes of S. pneumoniae but nevertheless included 90% of the antibiotic-resistant strains at the time of licensing in 2000. Numerous studies have shown the success of PCV7 at reducing the carriage of these serotypes. For example, in one study from Portugal, there was a clear reduction in the carriage of drug-resistant vaccine serotypes in daycare centres using the vaccine compared with control centres without vaccination (Pediatr Infect Dis J 2005;24(3):243-52). However, replacement by other disease-causing strains not covered by the vaccine was observed. “We have to be careful about interpreting this because the number of isolates that were resistant did actually decrease from 80 to 21, so although other resistant strains emerged, their absolute frequency decreased,” remarked Dr. Keith Klugman, Emory University, Atlanta, Georgia.

A number of studies have documented a decline in resistance after the introduction of PCV7. For example, a study by the Northern California Kaiser Permanente care organization showed how full penicillin resistance for all ages decreased from 15% in 2000 to 5% in the second quarter of 2003 (Pediatr Infect Dis J 2004;23(6):485-9). “The vaccine was also able to reduce antibiotic use, and clearly this is a synergistic benefit of the vaccine,” stated Dr. Klugman.

There is extensive evidence that carriage of resistant strains and antibiotic use and resistance decreased after introduction of the vaccine. Studies have also shown that invasive disease due to S. pneumoniae serotypes covered by PCV7 declined among children under 5 (J Infect Dis 2010;201(1):32-41). Interestingly, invasive disease also declined among adults aged over 65 years, suggesting that vaccination of the young provided some degree of herd immunity for adults.

Such evidence of an effect on invasive disease is, however, circumstantial. “The only clinical trial that directly showed the effect of a vaccine on invasive pneumococcal disease in children was done in South Africa,” explained Dr. Klugman. The study included 40,000 children, many of whom were infected with HIV (N Engl J Med 2003;349(14):1341-8). Approximately half received a 9-valent conjugated vaccine and the rest received placebo. There was a 67% reduction in the incidence of invasive pneumococcal disease caused by penicillin-resistant strains and a 66% reduction in disease caused by cotrimoxazole-resistant strains.

Serotype Replacement

Although there was a reduction in resistant strains after the introduction of PCV7, the serotype replacement phenomenon is a real threat. While resistance did show a decline in the first few years after the introduction of the vaccine, in more recent years there appears to be a slight upward trend in resistance. Interestingly, according to Dr. Klugman, “This [upward trend] is observed in young children; you don’t see the same trend upwards in older patients, suggesting that the selection for resistance is taking place in children.”

The driver of resistance is the replacement of resistant strains covered by the PCV7 vaccine with non-vaccine serotypes that develop resistance under the selective pressure of antibiotic use. The best known of these replacement serotypes is serotype 19A. In 2000, between 2 and 3 cases of serotype 19A per 100,000 population were reported in children under 5 but by 2006, there were almost 10 cases per 100,000 (J Infect Dis 2008;197(7):1016-27).

To understand what drives serotype replacement and what factors influence the speed at which it occurs, it is useful to consider the evolutionary mechanisms of colonization dynamics. Resistance can evolve through mutations, recombination (bacteria that swap genes) and mobile genetic elements. “An increase in clonal diversity and cell density increases the ‘evolvability’ of these bacteria,” explained Dr. Fernando Baquero, Ramón y Cajal University Hospital, Madrid, Spain. Any reduction in cell density of mucosal colonies and the number of serotypes would, in theory, slow evolution towards resistant serotypes.

Experience with PCV7 suggests that PCV13 will not be the definitive answer. In the words of Dr. Klugman, “The story of pneumococcus is still with us, and we will need further development of conjugate vaccines… to deal with emergent strains.” Nevertheless, the additional serotype coverage of the new 13-valent vaccine includes most of the serotypes to have emerged after the introduction of PCV7. In particular, serotype 19A is included.

According to Dr. Ralf René Reinert, Pfizer Pharmaceuticals, Paris La Défense, France, the technology used in the development of PCV13 was based on PCV7 which has been safely administered in millions of doses since its launch. Clinical development of PCV13 involved several phase III trials to assess different dosing schedules (3+1, 2+1, 3+0), vaccination of older children, a transition study (PCV13 following PCV7) and immune response when administered concomitantly with other vaccines. The complexity of the development program reflected the need to demonstrate efficacy and safety in numerous scenarios.

The new vaccine had to demonstrate immunogenicity (defined as IgG antibody concentration =35 mg/mL) for all the serotypes included. In a trial in Germany that compared the PCV7 and PCV13 vaccines, there were no differences in immunogenicity for the serotypes in PCV7 for the primary series.

Adult Vaccination

As noted by Dr. Giuseppe Cornaglie, University of Verona, Italy, “People aged over 65 years will soon outnumber children under 5 for the first time in history.” These older individuals are at greater risk of community-acquired pneumonia (CAP) and mortality is disproportionately higher, due largely to concurrent conditions such as diabetes and chronic lung disease. A 23-valent polysaccharide vaccine (PPV23)—the current standard of care—has been licensed for adults since 1983. Nevertheless, immunogenicity of this vaccine is often low, and a conjugate vaccine may provide a greater immune response. In a study comparing PCV7 and PPV23 for most serotypes covered by the conjugate vaccine, immunogenicity was indeed significantly greater (Clin Infect Dis 2008;46(7):1015-23). Consequently, the decision was made to develop an adult PCV13 vaccine in parallel to the pediatric program. For registration purposes, PCV13 has to demonstrate at least non-inferiority with respect to PPV23. The results of the registration trials are expected this year.

Summary

After the introduction of PCV7 for young children, a marked decrease in invasive pneumococcal disease and antibiotic resistance was observed. However, serotype replacement phenomena have gradually eroded the benefit, thereby justifying the development of the PCV13 vaccine, which extends coverage to emerging drug-resistant serotypes.