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PRIORITY PRESS - Association of Medical Microbiology and Infectious Disease Canada- Canadian Association for Clinical Microbiology and Infectious Diseases (AMMI-CACMID) Annual Conference

Montreal, Quebec / April 7-9, 2011

The direct and indirect effects of introducing the 7-valent pneumococcal conjugate vaccine (PCV-7) into the routine childhood vaccination program on invasive pneumococcal disease (IPD) have been dramatic. Following its introduction in children under the age of 5 years in Quebec, “Vaccine coverage reached almost 100%,” confirmed Dr. Louis Valiquette, Associate Professor of Microbiology and Infectious Diseases, Université de Sherbrooke, Quebec, here at AMMI-CACMID, “and there was a rapid decrease in IPD following the introduction of the vaccine mainly in children <5 years.” For example, from a rate of approximately 60 IPD cases/100,000 person-years in 2004 prior to the introduction of the PCV-7 vaccine program, IPD rates were essentially halved following the introduction of the vaccine to approximately 30 cases of IPD/100,000 person-years in children <5. A significant 13% reduction in pneumonia among Quebec children <5 years was also seen following the PCV-7 universal program. The same vaccination program led to a “quite convincing” reduction in otitis media in the same age group as well. Indirectly, the PCV-7 vaccine has reduced pneumococcal colonization rates among immunized children, resulting in a substantial reduction in IPD rates in infants under 90 days of age.

Similarly, routine PCV-7 vaccination programs have led to significant reductions in IPD adults =65 years. In one Calgary-based study, for example, Kellner et al. observed a 28% overall reduction in IPD between 1998 to 2007; IPD due to isolates contained in the vaccine fell to almost zero. Dr. Valiquette and colleagues observed a similar pattern in IPD reductions among adults residing in Sherbrooke, where PCV-7 serotype-related IPD dropped from a high of 30 cases in 1999 to a low of about 5 cases in 2007. In the US, IPD rates have dropped by 65% among unvaccinated adults >65 years compared to rates seen prior to the introduction of the PCV-7 vaccine in childhood.

In contrast, there is little evidence either in Canada or in the US that the same routine childhood PCV-7 vaccination program has had a significant impact on community-acquired pneumonia (CAP) in adults >65 years where the burden of Streptococcus pneumoniae-CAP remains high.

Results with the 23-valent PPV

Currently in Canada, the 23-valent pneumococcal polysaccharide vaccine (PPV-23) is recommended for all patients over the age of 65, those with comorbidities such as underlying lung disease, the homeless and intravenous drug users. In a recent study (Clin Infect Dis 2010;51:15-22), Johnstone et al. investigated whether the PPV-23 reduced mortality or additional hospital admissions for potentially vaccine-preventable infections among older adults at high risk for CAP. A total of 2950 patients, mean age 68 years, were followed for a median of 3.8 years. Only one-third of the cohort actually received the PPV-23 vaccine, 70% prior to hospital admission and 30% during admission.

After discharge, almost half of the cohort had died during follow-up and 17% were admitted with vaccine-preventable infections. Some 55% overall reached the composite end point of all-cause mortality or additional hospitalization for vaccine-preventable infections. Importantly, receipt of the PPV-23 vaccine was not associated with a reduced risk of reaching the composite end point, at an adjusted hazard ratio of 0.91. Whether the new higher valent PCV-13 conjugate vaccine can offer better protection against S. pneumoniae in older adults is not yet known but there are hints that it may be more effective than the PPV-23 vaccine.

As discussed by Dr. Brian Ward, Associate Director, McGill Centre for Tropical Diseases, and Chief, Division of Infectious Diseases, MUHC, Montreal, Quebec, data from Canada and the US have clearly demonstrated that the PCV-7 conjugate vaccine in childhood can prevent IPD in adults. “If we see a similar benefit from the introduction of the PCV-13 vaccine program in children on IPD in the elderly, then we might expect we would see significant benefit in reducing IPD in adults,” he observed.

Some 13 randomized comparative studies have been carried out involving 2231 healthy adults, HIV patients and stem-cell transplant recipients. All of the trials compared the PPV-23 vaccine and the PCV-7 conjugate vaccine; little comparative data are yet available on the PCV-13 vaccine although some will be forthcoming over the next couple of years.

“Compared to the PPV vaccine, we have learned in general that the conjugate vaccines appear to elicit, on average, more IgG, so you get more antibody with the conjugate vaccines,” Dr. Ward noted. The antibodies elicited by the conjugate vaccines also have more avidity than antibodies elicited by the PPV-23 vaccine, he added, and they demonstrated better opsonophagocytic activity than PPV-elicited antibodies (opsonophagocytic activity is one of the main measures of functional antibody activity).

“Antibodies also persist slightly longer,” he told delegates here at AMMI-CACMID, “and very importantly, conjugate vaccines do not induce a hyporesponsive state—in other words, booster responses are not suppressed by prior immunization.”

Significant Findings

In one study of 219 elderly subjects >70 years (Clin Infect Dis 2008;46:1015-23), functional antibody titres were highest after 2 doses of the PCV-7 vaccine but patients who received the conjugate vaccine followed by the PPV-23 vaccine had higher antibody titres than those who received the PPV-23 vaccine first followed by the conjugate vaccine.

“This is quite significant and it may be very important for elderly subjects who have already received the vaccine,” Dr. Ward observed. Similarly, HIV subjects who received the pneumococcal conjugate vaccine plus the PPV-23 vaccine had a “clear advantage” over those who received the PPV-23 vaccine alone where antibody responses to serotypes shared between the 2 vaccines were higher and lasted slightly longer in those who received the combination strategy.

“If price were no object, we would already be using the highest valency conjugate vaccine followed by the PPV vaccine and in clinical practice, that is what I am doing: If I have a patient who is immunocompromised, I will use the highest valency conjugate vaccine followed by the PPV-23 vaccine because I think that is the best combination,” Dr. Ward reported during the scientific sessions. “So I wait one month, then I follow with the PPV-23 vaccine because these are the people you are most worried about and you want to give them the best chance they’ve got of being protected.”

Dr. Karl Weiss, Clinical Professor of Medicine, Université de Montréal, also noted during AMMI-CACMID that while the PPV-23 vaccine may not prevent pneumonia in older adults, “if they get the PPV-23 vaccine, it will lower the risk of them having bacteremia and it’s the bacteremic S. pneumoniae that kills, so at least if you can lower the rate of invasive infection, it’s already good.”

Clinicians are now debating whether to extend the use of these conjugated vaccines to adults to lower the rates of IPD in adults. “It makes sense but we have to prove it,” Dr. Weiss stated, adding, nevertheless, that if he were 65 today, “I would get the conjugated vaccine and the younger you are when you get these vaccines, the better the response is.”

Summary

S. pneumoniae remains an important pathogen against which a number of vaccines are available to protect children and adults >65 against invasive infection. The PCV-7 vaccine has already been shown to dramatically reduce the incidence of IPD in children and in older adults, although not CAP in adults. Whether the higher valency PCV-13 vaccine will further reduce IPD incidence remains to be seen, but early signs suggest that the PCV-13 conjugate vaccine may be associated with better protection against invasive disease in older adults than the PPV-23 vaccine. Until there is clear evidence to support the preferential use of the PCV-13 vaccine in older adults, the PCV-13 vaccine, followed one month later by the PPV-23 vaccine, appears to offer the greatest protection for older adults, especially those who are immunocompromised.