Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial

Reply:
To the Editor:

We appreciate the constructive comments of Suzuki et al about our previous work. First, it is important to clarify that the primary endpoint of this study was to assess whether the 23-valent pneumococcal polysaccharide vaccine (PPV23) can reduce the incidence of all-cause pneumonia and pneumococcal pneumonia [1]. Another purpose was to evaluate the number of deaths among all cases of pneumonia but it was not our purpose to evaluate the number of deaths among all subjects [1]. Comparison of results between the vaccine (13/63=20.6%) and placebo (26/104=25%) groups showed no significant difference (p=0.5181) indicating that vaccination was unable to reduce all-cause pneumonia-related mortality [1]. Suzuki et al pointed out that all-cause pneumonia related death was reduced but that other diseases-related death was increased by PPSV23 administration. We agree that the number of death was reduced in the vaccine group, and the result can be explained by 44.8% reduction of all-cause pneumonia [1].

The major concern of Suzuki et al appears to be the possibility that the increased number of deaths in the vaccine group compared to placebo group may be a vaccine-related adverse event. The criterion for vaccine-related adverse event was its appearance within 28 days after vaccination [1]. There was only one death within this period, and the patient was a 93-year-old elderly woman whose death was caused by her underlying congestive heart failure but not by vaccination. To further address the question of the authors we prepared Table 1 where the causes of death after 28 days of vaccination are detailed. All-cause pneumonia-related death was significantly (p<0.05) reduced in the vaccine group (13/502=2.6%) compared to the placebo group (25/504=5%). On the other hand, pneumonia-unrelated mortality was caused by a variety of diseases in both groups. There was no significant difference between the vaccine and placebo groups when pneumonia-unrelated deaths was analyzed by individual disease group; but analysis including death caused by all systemic diseases disclosed more significant number of pneumonia-unrelated deaths in the vaccine group than in the placebo group. The explanation for this observation is unknown. No study has previously shown that the presence of underlying diseases may increase mortality after PPSV23 vaccination.

Comparable observations were done in previous clinical trials. During the randomized clinical trial of 7 valent pneumococcal conjugated vaccines in HIV-infected patients, compared to the vaccine group, patients of the placebo group showed more significant number of serious adverse events [2]. In another randomized clinical trial of PPSV23 in HIV patients, paradoxically, the group undergoing vaccination had significantly increased frequency of pneumonia compared to the placebo group [3]. The mechanism of these adverse episodes is unclear but rather than vaccine-associated side effects, it is most probable that, they result from alteration of the systemic conditions of the patients [3]. Similar considerations apply to patients of our study because they had also compromised systemic conditions due to advanced aging and underlying disorders, and thus the risk of dying for other causes rather than pneumonia is high as previously suggested [4]. The fact that the Center for Disease Control and Prevention still continues recommending PPSV23 vaccination despite the observation of more frequent cases of pneumonia in the vaccine group than in the placebo group in a previous clinical trial supports our current argument [3].

In summary, the increased number of pneumonia-unrelated deaths reported in our study was not related to PPSV23 vaccination. The precise mechanism is unclear but a review of the current literature supports the idea that the compromised systemic condition of our patients was an important risk factor for this unsatisfactory outcome.

References

1. Maruyama T, Taguchi O, Niederman MS, et al. Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial. BMJ 2010;340:c1004 doi: 10.1136/bmj.c1004[published Online First: Epub Date]|.
2. French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. N Engl J Med 2010;362(9):812-22 doi: 10.1056/NEJMoa0903029[published Online First: Epub Date]|.
3. French N, Nakiyingi J, Carpenter LM, et al. 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet 2000;355(9221):2106-11
4. Fekete T. ACP Journal Club. Pneumococcal vaccine reduced pneumococcal pneumonia and associated mortality. Ann Intern Med 2010;152(12):JC6-5 doi: 10.7326/0003-4819-152-12-201006150-02005[published Online First: Epub Date]|.

Authors:
Takaya Maruyama,
Staff Physician,
Department of Respiratory Medicine, National Hospital Organization Mie National Hospital, Tsu, Mie, Japan.

Tetsu Kobayashi
Associate Professor
Department of Pulmonary and Critical Care Medicine
Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Corina N. D' Alessandro-Gabazza
Assistant Professor
Department of Immunology
Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Esteban C. Gabazza
Professor and Head
Department of Immunology
Director,
Center for Intractable Diseases,
Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Corresponding author: gabazza@doc.medic.mie-u.ac.jp

Osamu Taguchi
Professor
Center for Physical and Mental Health
Mie University Graduate School of Medicine, Tsu, Mie, Japan.