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 doi: https://doi.org/10.1136/bmj.c1004 (Published 08 March 2010) Cite this as: BMJ 2010;340:c1004
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
To the Editor:
In 2014, the 23-valent pneumococcal polysaccharide vaccine (PPV23) was incorporated into the nationally recommended vaccines for adults aged ≥65 years in Japan. It would not be surprising if the randomized-controlled trial in nursing homes presented by Maruyama et al. [1] had a significant influence on this policy. However, we have a concern about the findings of their study.
In the abstract of their paper, the authors stated that “the death rate from all cause pneumonia (vaccine group 20.6% (13/63) v placebo group 25.0% (26/104), P=0.5) and from other causes (vaccine group 17.7% (89/502) v placebo group (80/504) 15.9%, P=0.4) did not differ between the two study groups”. This statement is misleading because the mortality data is not properly presented. We recalculated the efficacy of PPV23 against mortality during the follow up period (mean 2.28 years) and found that although PPV23 decreased the mortality related to all cause pneumonia by 50% (95% CI: 3% to 74%) it increased the mortality related to other causes by 41% (95% CI: 2% to 96%) (Table). It indicates that for each year 89 older people need to be vaccinated to prevent one death from pneumonia but that for every 52 older people vaccinated there is one extra death from a condition unrelated to pneumonia.
According to a recent meta-analysis, the beneficial effect of PPV23 against pneumonia-related mortality has not been confirmed in previous trials [2-4], except for the authors’ trial [5]. Considering its substantial impact on the public health policy in Japan and other countries, the authors are urgently requested to make the complete trial data publicly available to examine the validity of their finding.
References:
1. Maruyama, T., 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: p. c1004.
2. Ortqvist, A., et al., Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet, 1998. 351(9100): p. 399-403.
3. Alfageme, I., et al., Clinical efficacy of anti-pneumococcal vaccination in patients with COPD. Thorax, 2006. 61(3): p. 189-95.
4. Kawakami, K., et al., Effectiveness of pneumococcal polysaccharide vaccine against pneumonia and cost analysis for the elderly who receive seasonal influenza vaccine in Japan. Vaccine, 2010. 28(43): p. 7063-9.
5. Diao, W.Q., et al., Efficacy of 23-valent pneumococcal polysaccharide vaccine in preventing community-acquired pneumonia among immunocompetent adults: A systematic review and meta-analysis of randomized trials. Vaccine, 2016. 34(13): p. 1496-503.
Authors:
Motoi Suzuki, MD MSc PhD
Assistant Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan
Konosuke Morimoto, MD PhD
Associate Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan
Christopher M. Parry, BA (Hons) MB BChir PhD FRCP FRCPath DTMH
Professor
School of Tropical Medicine and Global Health, Nagasaki University, Japan/London School of Hygiene and Tropical Medicine, United Kingdom
Koya Ariyoshi, MD MSc PhD
Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan
Competing interests: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University has received research funding from Asahi Kasei Pharma, Dainippon Sumitomo Pharma, Pfizer, and Taisho Toyama Pharmaceutical.
Marayuma et al have recently reported findings of their study
demonstrating efficacy of the 23-valent pneumococcal polysaccharide
vaccine (PPV) in preventing pneumococcal pneumonia in nursing home
residents in Japan.(1)
We wish to report results of a retrospective audit of patients with
invasive pneumococcal disease admitted to a District General Hospital in
England that, contrary to Marayuma’s work, suggest vaccine failure of the
23-valent PPV in preventing invasive pneumococcal disease (IPD).
Streptococcus pneumoniae is a significant pathogen and to date 90
different serotypes have been identified. It is the commonest cause of
community-acquired pneumonia and is associated with considerable morbidity
and mortality.(2) Department of Health (DOH) guidance recommends
vaccination of specific high risk category groups and all patients >65
years of age with 23-valent PPV.(3)
The aim of the audit was to investigate clinical cases of IPD,
documenting prior vaccination status and the pneumococcal serotype causing
disease for each patient (Serotyping was performed by the Respiratory and
Systemic Infection Laboratory, Health Protection Agency, Colindale,
London).
Over an 18-month period (September 2006 - February 2008) 37 adult
patients (age range: 41-91 years) were diagnosed with IPD (Streptococcus
pneumoniae isolated from normally sterile sites including blood, joint
fluid and CSF). Pneumonia was the predominant clinical focus (n=34), two
patients had pneumococcal septic arthritis and one case had meningitis.
31 study patients satisfied DOH criteria for prior PPV immunisation
(25 over the age of 65 years). Vaccination status was available for 28 of
these patients, of whom 17 had received the 23-valent PPV and 11 patients
had never been immunised. Within the sub-group of 17 vaccinated cases, 15
patients had invasive infection due to a recognised serotype contained
within the 23-valent PPV, implying failure of the vaccine in preventing
invasive pneumococcal disease in these patients. Of the 11 unvaccinated
patients nine had clinical isolates of known serogroups contained within
PPV. Thus in total 24 out of 28 patients had invasive disease due to
current PPV serotypes.
Prior to conducting this audit we perceived that the majority of
patients admitted with proven pneumococcal disease would not have been
vaccinated. Results surprisingly demonstrated that, despite being
vaccinated, many patients were not sufficiently protected against
serotypes contained within the 23-valent vaccine and subsequently had
proven pneumococcal infection. In contrast to the work of Marayuma et al,
our study concludes that the efficacy of 23-valent PPV was suboptimal.
Unlike conjugate vaccines, it is well recognised that polysaccharide
vaccines do not promote immunological memory or provide long-lasting
protection.(4) Pneumococcal disease has considerable impact on hospital
activity, especially during winter months. Our study suggests that further
work is required to establish a superior vaccination strategy, in adults,
against this significant pathogen.
References
1. Takaya Marayuma, Osamu Taguchi, Michael S Niederman 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
3. Salisbury, Ramsay, Noakes. DOH 2006. Immunisation Against
Infectious Disease (The Green Book)
4. Musher DM, Rueda AM, Nahm MH et al. Initial and subsequent
response to pneumococcal polysaccharide and protein-conjugate vaccines
administered sequentially to adults who have recovered from pneumococcal
pneumonia. J Infect Dis 2008 Oct 1;198(7):1019-27
Competing interests:
None declared
Competing interests: No competing interests
We read with interest the recent trial of the 23-valent pneumococcal
polysaccharide vaccine (PPV) in a Japanese nursing home, where the
vaccine showed 63.8% efficacy in preventing pneumococcal pneumonia. There
was no invasive pneumococcal disease in the vaccinated group (1). In
Scotland a recommendation was made in October 2003 that all those aged 65
or over should be given PPV. We examined retrospectively cases of
pneumococcal bacteraemia in this age group over the subsequent 5 years in
Tayside (2004-2008 inclusive). There were 108 Streptococcus pneumoniae
bacteraemias in this age group. 97 cases (90%) were caused by serotypes
included in the PPV, and of these 30 (31%) patients had been previously
vaccinated with PPV (mean 35.4 months previously, range 2-82 months). 19
cases (20%) had never been vaccinated, but due to difficulties in tracing
medical records the vaccination status of the remaining 48 (49%) could not
be determined. For the same reason we were not able to collect data on
mortality and underlying chronic illness. Nevertheless we found that
nearly one third of S.pneumoniae bacteraemias in the elderly were in
patients who had been previously vaccinated, which seems very high in the
light of a recent meta-analysis which showed vaccine efficacy to be 74%
(2). This may be explained however by the fact that trials assessing PPV
have not performed follow-up beyond 3 years. In our 30 bacteraemia cases,
19 occurred more than 3 years after vaccination, likely reflecting a
reduction in efficacy over time (3). We believe that the new pneumococcal
conjugate vaccines now need to be assessed in this setting as the
polysaccharide vaccine is not sufficiently effective.
William J Olver
Lasantha Ratnayake
References
1. Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H,
Kobayashi T 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
2. Moberley S, Holden J, Tatham D, Andrews R. Vaccines for preventing
pneumococcal infection in adults. Cochrane Database Syst Rev
2008;(1):CD000422
3. Jackson LA, Janoff EN. Pneumococcal vaccination of elderly adults:
new paradigms for protection. Clin Infect Dis 2008;47:1328-1338
Competing interests:
None declared
Competing interests: No competing interests
Maruyama et al. (1) conclude in their paper that vaccination with
23-valent pneumococcal polysaccharide vaccine reduced mortality from
pneumococcal pneumonia in nursing home residents and state that their
study demonstrates the need for routine vaccination .
On the other hand, the death rate for all cause pneumonia and non-
pneumococcal pneumonia in vaccine group did not differ significantly with
respect to placebo, suggesting that high risk patients developed fatal
pneumonitis caused by agents other than pneumococci. Routine usage of the
vaccine may lead to long- term emergence of other agents, or of
pneumococcal strains other than the subtypes included in the vaccine (2),
consequently reducing vaccine effectiveness in the longer term. Thence,
this study is not conclusive and further studies are needed in order to
clearly ascertain the need of systematic vaccination and long term
consequences of immunization campaigns.
References
1. Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H 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 Mar 8;340
2. Goldman B. VACCINES FOR SENIORS Chalk up at least part of the
expansion of life expectancies in developed countries to the advent of
childhood vaccinations.
http://stanmed.stanford.edu/2009spring/article9.html (last accessed on
March 15th, 2010)
Competing interests:
None declared
Competing interests: No competing interests
Mortality unrelated to vaccine during long-term follow-up
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.
Competing interests: No competing interests