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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 8th Canadian Immunization Conference

Toronto, Ontario / November 30-December 3, 2008

As reported here this week during the CIC sessions, the 7-valent pneumococcal conjugate vaccine (PCV7) has had a significant effect on invasive pneumococcal disease wherever it has been introduced. With a 97% efficacy rate against the disease caused by the seven serotypes in the vaccine, researchers reported that the rate of invasive pneumococcal disease here in Canada has decreased by 81.6% for all serotypes, by 92.6% for PCV7 serotypes and by 93.4% for PCV7 and related serotypes within the same serogroup (Kellner et al. CMAJ 2005; 173(10):1149-51).

In the US, evidence for herd immunity exists in children outside of the vaccinated age range, reducing invasive disease rates by approximately 50% in infants under two months of age, as well as in children between 5 and 17 years of age, as discussed by Dr. Steven Black, Professor of Pediatrics and Infectious Disease, Center for Global Health, Cincinnati Children’s Hospital, Ohio. Herd immunity has also reduced invasive pneumococcal disease among adults between the ages of 65 and 70 years, where the effect of vaccinating children has had a more marked effect on the incidence of invasive pneumococcal disease than directly vaccinating older adults against pneumococcal disease, Dr. Black pointed out.

Conversely, there has been an increase in disease caused by non-vaccine serotypes, he added. For example, between 1998-1999 and 2006, the PCV7 vaccine had reduced vaccine-type disease by 89% in adults <u>></u>65 years of age in the US, but disease from non-vaccine serotypes increased by 34% over the same interval. Whether this increase is directly or indirectly linked to the widespread introduction of the PCV7 vaccine is not clear. As Dr. Black noted, referring to vaccine serotype frequency between 1979 and 1996 in Spain, “You see a lot of variability in certain serotypes in terms of their frequency over a long time interval and this was during a time when the vaccine was not in use.” Again, prior to the use of the PCV7 vaccine, the per cent of 19A isolates submitted to a reference lab in Korea increased substantially and then dropped equally drastically—“All without vaccine use in Korea,” Dr. Black observed.

The strongest data indicating that the vaccine was not the main cause was the lack of replacement disease seen in the White Mountain Apache children following introduction of the PCV7 vaccine. After its introduction, researchers reported a 92% reduction in the rate of infectious pneumococcal disease in the vaccinated cohort under the age of five but there was no corresponding increase in replacement disease due to serotype 19A (Lacapa et al. Clin Infect Dis 2008;47(4):476-84). Interestingly, when the authors examined antibiotic use in the study population, only 12 children had received azithromycin during the year of 2007, suggesting that antibiotic pressures may be contributing to the changing sero-epidemiology of pneumococcal disease as well.

“The PCV 7 vaccine has had a dramatic direct and indirect effect on pneumococcal disease but the sero-epidemiology of the pneumococcus also varies dramatically over time,” Dr. Black concluded. “Ongoing surveillance will be necessary and it may be that we need to revisit the composition of our vaccines every so often [to keep up with the changing sero-epidemiology].”

Acute Otitis Media

The PCV7 vaccine has resulted in significant reductions in invasive pneumococcal disease with virtual elimination of disease due to the seven vaccine serotypes, yet the same cannot be said for acute otitis media (AOM). Initial clinical trials on direct protection against AOM from the PCV7 vaccine indicated only a 6% to 7% reduction in AOM following immunization, although the vaccine did reduce pneumococcal AOM by about one-third. Better appreciation of how children, especially the very young and particularly young aboriginal children, are at such a high risk for AOM may help with future efforts to reduce the burden of disease.

As discussed by Dr. Stephen Pelton, Professor of Pediatrics and Epidemiology, Boston University Schools of Medicine and Public Health, Massachusetts, age is one of the “critical risk factors” for AOM. Between 6 and 11 months of age, 36% of infants have an episode of AOM vs. 29% of infants between 12 and 23 months and 15% of children between 24 and 35 months of age following an upper respiratory tract infection. “About one-third of infants end up with AOM after a viral respiratory tract infection,” he added, which is a reflection of both the naivety of the young child’s immune system and the immaturity of their Eustachian tube function. Together these risk factors enable bacteria to ascend into the middle ear. Early disease is also an important risk factor for recurrent AOM, “Which is why we have to think about how we are going to prevent disease early,” Dr. Pelton told delegates. The degree to which the nasopharyngeal passages are colonized with otopathogens also plays a major role in predisposing children to AOM—the greater the number of otopathogens present, the higher the risk of AOM.

Immunization could potentially contribute to a significant reduction in AOM through two separate mechanism: first, by reducing colonization rates from Streptococcus pneumoniae, Moraxella catarrhalis and non-typable H. influenzae (NTHi), the key otopathogens behind AOM, and secondly, by eliciting protective antibody responses to these pathogens, so that even if bacteria invade the middle ear, they could be eradicated before purulent otitis develops. As Dr. Pelton went on to demonstrate, H. influenzae is an important global pathogen in AOM. Data from children in Rochester, New York, who had received the PCV7 vaccine and were followed from six months onwards showed that whether children had infrequent or recurrent AOM, “the most common bacterial pathogen was NTHi in both groups,” he reported. Thus, a vaccine that targets both pneumococcus and H. influenzae has the potential to reduce more episodes of AOM than a single pathogen vaccine.

The POET (Pneumococcal Otitis Efficacy Trial) evaluated a new 11-valent pneumococcal vaccine conjugated to protein D from NTHi. At follow-up, results showed that the dual-pathogen vaccine reduced clinical episodes of AOM by approximately 33% and the incidence of culture-confirmed AOM by approximately 42%, “suggesting that there is about a twofold further reduction in AOM with the pneumococcal vaccine conjugated to protein D than the pneumococcal conjugate vaccine alone when adjusted for the differences in study design,” Dr. Pelton observed.

Laboratory work cited by Dr. Pelton also suggests that there is potentially some functional activity against 19A disease in children who have been immunized with the 11-valent pneumococcal vaccine conjugated to protein D conjugate, even though it does not contain the 19A serotype. Thus, there may be what might be referred to as “cross-protective” activity from the 11-valent pneumococcal vaccine conjugated to protein D from NTHi against serotypes that cause disease in the community but which are not included in the vaccine. Further clinical trials and post-marketing studies will be needed to determine if the laboratory findings translate to clinically relevant protection against disease due to serotype 19A.

Summary

The fact that there have been declines in both invasive pneumococcal disease as well as in AOM is an important observation, as it partly reflects the fact that non-vaccine serotypes have far less capacity to cause pneumococcal otitis and invasive disease. As indicated by Dr. Pelton, it has been suggested that non-vaccine serotypes are fivefold less capable of causing invasive disease compared with vaccine serotypes and about twofold less capable of producing AOM, although this is not true for all emerging vaccine serotypes. “Further reduction in AOM will require expanded valency pneumococcal vaccines, targeting of additional pathogens and prevention of early-onset disease through herd immunity,” Dr. Pelton concluded. “I would suggest that the next major advance in the prevention of AOM is likely to be a dual pathogen vaccine because NTHi is a frequent cause of AOM [and its recurrence], so its prevention has the potential to substantially reduce the burden of disease from AOM.”