PCV13 vs Placebo: Efficacy Tested in New Trial

Andrew F. Shorr, MD, MPH


April 15, 2015

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This is Andy Shorr, from the Washington Hospital Center in Washington, DC, with a pulmonary and critical care literature update.

I'd like to point out an article by Mark Bonten and colleagues[1] in the March 19 issue of the New England Journal of Medicine. This report describes the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA).

CAPiTA is a randomized controlled trial that studied a new vaccine, pneumococcal conjugate vaccine (PCV13), for preventing pneumonia in adults 65 years of age or older.

Community-acquired pneumonia (CAP) remains a huge issue in this country and pneumococcus still remains the leading pathogen. In the United States, we have an older vaccine that's commercially available: pneumococcal 23-valent polysaccharide vaccine (PPV23).[2] And although there are recommendations from the Advisory Committee for Immunization Practices of the Centers for Disease Control and Prevention about whom to give this vaccine,[3] the actual evidence that supports use of this older vaccine is limited.

There's not even evidence that PPV23 prevents pneumococcal disease.[4] It may prevent invasive pneumococcal disease, particularly bacteremia.[4] But in terms of actual pneumonia or pneumococcal pneumonia, it's not clear that the vaccine is very effective.

There are also immunogenic concerns about the vaccine, specifically as it relates to the recommendations about re-vaccination, because it may actually diminish the immune system somewhat rather than enhance it with re-vaccination.[5] This is all theoretical and based on studies looking at immune cell functions as opposed to clinical trial outcomes.

A lot of the recommendations about the older PPV23 vaccine are not based on the best-quality evidence.

That's what led to this trial with the newer vaccine by Bonten and colleagues, where they randomized more than 84,000 patients—that's huge—in The Netherlands to either placebo or PCV13. Why, ethically, could they use placebo? Because they don't use the older PPV23 vaccine that we have here in America. They don't think it's adequate. They don't offer it at all to their patients who are 65 years of age or older.

In this trial,[1] they randomized patients who were 65 years or older to PCV13 or placebo. They then looked over a 5-year follow-up period at rates of actual pneumococcal pneumonia, invasive pneumococcal disease—the rates of infection due to the vaccine-specific serotypes, which were included in the PCV13 vaccine—and they also looked overall at rates of just CAP.

They had a blinded adjudication committee evaluating things to lend quality to the evaluation of whether patients had pneumonia or not. Important to note is that about 1600 patients in each arm of the roughly 42,000 that were randomized to each arm showed up during the up to five year follow-up period for evaluation of pneumonia. There wasn't even a hint of a referral or a selection bias in terms of who was evaluated for CAP.

Patients who were in the trial and showed up with pneumonia symptoms all underwent evaluation that included specific urinary antigen testing for the serotypes that were of interest in this trial, besides just the pneumococcal urinary antigens we have available to us in our routine clinical practice. The patients also all had blood cultures, etc.

When the investigators looked at the data during the follow-up period, they found that the rates of pneumococcal disease specifically due to those serotypes were reduced by nearly 50%. If not more impressive, rates of invasive disease were reduced by more than 70%.[1] The vaccine actually achieved its objective, giving us good evidence, with a placebo comparison, that this vaccine reduced rates of pneumococcal disease and the burden of pneumococcal illness.

There was, of course, no difference in deaths in the study. The trial was underpowered for that. Patients who showed up for evaluation were evaluated and treated promptly, which of course reduces rates of infectious disease–related deaths.

When the investigators looked only at rates of CAP—irrespective of the pathogen—they saw no difference between the vaccinated and the placebo groups. Again, you wouldn't expect PCV13 to necessarily reduce rates of CAP due to Haemophilus influenzae. There would be no reason to suspect that, but it may redistribute air in the balloon. In other words, you may reduce rates of pneumococcal disease with this vaccine but you don't reduce overall CAP rates. It perhaps shifts the pathogens to include in the placebo arm more non-pneumococcal infections. You may not be reducing rates of CAP; you're just reducing the most severe forms of pneumococcal disease in terms of invasive disease—specifically, just pneumonia due to these strains of pneumococcus.

Overall, the investigators saw no issues about safety or later immune dysfunction. That's with up to 5 years of follow-up, which gives us pretty healthy data about the safety profile of the PCV13 vaccine.

Again, if you check you'll see ACIP's latest recommendations for use of this vaccine.[2] The CAPiTA study is perhaps the best-quality, large trial ever done on pneumococcal prevention using a vaccine. As pulmonologists, as intensivists, it's something we need to be aware of. I urge you to read this article that was in the New England Journal of Medicine.[1]

This is Andy Shorr from Washington, DC. Please leave your comments below.


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