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PRIORITY PRESS - 9th Canadian Immunization Conference (CIC)

Quebec City, Quebec / December 5-8, 2010

According to statistics from the Public Health Agency of Canada (PHAC), the highest rates of invasive pneumococcal disease (IPD)/100,000/year are seen in infants under the age of 1, after which rates continue to decline until about the age of 65, and begin to increase again.

As discussed here at the CIC by Dr. Jennifer Johnstone, Assistant Professor of Infectious Disease, McMaster University, Hamilton, Ontario, S. pneumoniae is estimated to cause approximately 30% of all cases of pneumonia. “Rates go up exponentially once patients reach the age of 65 and the burden of S. pneumoniae-community-acquired pneumonia (CAP) is high,” she explained.

Two vaccine strategies are in place aimed at reducing the burden of IPD in adults. Around 2002 (depending on the province), infants received the 7-valent pneumococcal conjugate vaccine (PCV7) at 2, 4 and 12 months of age. “Even though only infants were given the vaccine, we saw rates of IPD come down in adults,” Dr. Johnstone told delegates. For example, in the US, rates of IPD between 1998 and 2003 in individuals between the ages of 50 and 64 dropped by 17% (PCV7 was licensed in 2000), by 29% in adults between the ages of 65 and 74, and by 35% in seniors between 75 and 84 years of age.

“The hypothesis for this was that there was a decrease in nasopharyngeal carriage of S. pneumoniae in children and we ended up with herd immunity,” Dr. Johnstone explained. Canadian data from Calgary support a diminishing trend in IPD among adults 65 years of age and older. Although not statistically significant, there was a modest 28% reduction in IPD in individuals =65 years of age between 1998 and 2007 following the introduction of PCV7 in 2002. “Most strikingly,” Dr. Johnstone added, “IPD due to isolates contained in the vaccine fell to almost zero.” However, IPD due to non-vaccine serotypes increased so the overall net effect of the PCV7 vaccination program was not as dramatic.

The other strategy long in place to prevent IPD in adults has been the use of the 23-valent pneumococcal polysaccharide vaccine (PPSV23). The vaccines are recommended for any patient over the age of 65, those with comorbidities (underlying lung disease) and for the homeless and intravenous drug users. “The issue with the polysaccharide vaccine has been in its uptake,” Dr. Johnstone noted. For example, one Toronto-based study (Al-Sukhni et al. Vaccine 2008;26:1432-7) found that only about one-third of eligible elderly in Ontario had received the polysaccharide vaccine.

In one of her own studies carried out in Edmonton (Arch Intern Med 2007;167:1938-43), Dr. Johnstone and colleagues found that only 22% of adults admitted to the hospital for CAP had been vaccinated against IPD. “We know this vaccine is safe and it is free for those at risk, but there continue to be questions about its efficacy,” she observed.

A number of meta-analyses have been carried out evaluating the efficacy of the polysaccharide vaccine, perhaps one of the more authoritative being a Cochrane review (Moberley et al. Cochrane Database Syst Rev 2008;1:CD000422). Based on 15 prospective randomized trials of the polysaccharide vaccine in adults, investigators concluded that the vaccine reduced the number of IPD cases by approximately 74% and among those who develop IPD, vaccination improved outcomes. At the same time, the polysaccharide vaccine does not prevent all-cause pneumonia or mortality.

Recently Published Study

In her own recently published study (Clin Infect Dis 2010;51:15-22), Dr. Johnstone and colleagues sought to determine whether the polysaccharide vaccine reduced mortality or additional hospital admissions for potentially vaccine-preventable infections including pneumonia, sepsis and meningitis in a cohort of adults at high risk for pneumonia. In an earlier study, Dr. Johnstone had found that 16% of all patients with a history of pneumonia were rehospitalized for repeat episodes, suggesting that if a patient has a history of pneumonia, they are at substantially increased risk of acquiring pneumonia again.

A total of 2950 patients, mean age 68 years, were followed for a median of 3.8 years. One-third had received the polysaccharide vaccine, 70% prior to hospitalization and 30% during hospitalization. Following discharge, 48% of the cohort died during the follow-up interval and 17% were readmitted for vaccine-preventable infections; overall, 55% reached the composite outcome of death or infection, “which was a lot and which surprised us,” Dr. Johnstone told delegates. Importantly, however, the polysaccharide vaccine was not associated with a reduced risk of the composite outcome compared with unvaccinated controls at an adjusted hazard ratio of 0.91. US data have demonstrated that antibody levels following polysaccaride vaccination in patients with a history of pneumonia return to baseline when measured 6 months later.

“Our current pneumococcal disease prevention strategy is suboptimal,” Dr. Johnstone concluded. “There is a problem with uptake, the vaccine is not thought to prevent pneumonia and it does not prevent pneumococcal disease in patients with a history of pneumonia. Better pneumococcal vaccination strategies are urgently needed.”

Currently, there is a very large-scale (approximately 85,000 adults), randomized controlled trial now underway in The Netherlands evaluating the 13-valent pneumococcal vaccine (PCV13), the only one to date to cover for serotype 19A, a major contributor to pneumococcal disease in adults and children in Canada.

SOS Network

As discussed by Dr. Shelly McNeil, Canadian Center for Vaccinology and Associate Professor of Medicine, Dalhousie University, Halifax, Nova Scotia, the PHAC/CIHR Influenza Research Network (PCIRN) was established to assemble research groups across the country to establish an infrastructure to test and evaluate a pandemic influenza vaccine should the need arise. The effort was funded just before the pandemic actually took hold, “so we established all of the mechanisms very rapidly to evaluate the vaccine during the pandemic,” she reported.

As Dr. McNeil noted, there are now some 10 sites in the PCIRN Adult Serious Outcomes Surveillance (SOS) Network. It also includes over 30 Canadian universities, hospitals and institutions in 6 provinces. In order to implement a new pneumococcal conjugate vaccine for Canadian adults, a thorough understanding of the burden of pneumonia and CAP among adults is required.

Canada currently lacks good data on serotype distribution, particularly in adults, as well as which serotypes are causing IPD in older patients. “We also need to understand the true burden of CAP and what proportion is caused by pneumococcus and by which serotypes,” she added. For these reasons, the SOS Network plans to report the frequency and serotype distribution of nasopharyngeal colonization of S. pneumoniae among adults admitted to sentinel Canadian hospitals for CAP.

They also plan to document baseline rates of hospitalized CAP and serotype-specific rates of colonization, pneumococcal pneumonia and IPD to allow them to evaluate the effectiveness of new vaccines following their implementation. Routine testing for the cause of CAP is not and will not be carried out, but investigators will encourage at least the use of swabs to look at S. pneumoniae in the nasopharynx.

“New vaccines offer tremendous potential to improve prevention of pneumococcal disease in Canadian adults,” Dr. McNeil concluded. “But the decision to replace the PPSV23 with new conjugates in publicly-funded programs for adults will be informed by evaluation of the epidemiology of S. pneumoniae in Canada. Right now, our understanding of the contribution of vaccine-preventable pneumococcal serotypes to IPD and CAP in adults is lacking.”

Summary

S. pneumoniae is an important pathogen in older adults, leading to approximately 30% of all CAP along with other significant vaccine-preventable infections. The currently available PPSV23 offers relatively good protection against IPD but it does not appear to prevent all-cause pneumonia or mortality, nor does it protect patients with a history of pneumonia against further episodes. This suggests that there is an important need for a more effective pneumococcal vaccine for older adults. Results from a large clinical trial in which PCV13 is being evaluated are eagerly awaited.