Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis

  • Review
  • Intervention

Authors


Abstract

Background

Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed.

Objectives

To assess the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms vaccines AND pseudomonas (last search 30 May 2013) and PubMed using the terms vaccin* AND cystic fibrosis (last search 30 May 2013).

Selection criteria

Randomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in cystic fibrosis.

Data collection and analysis

The authors independently selected trials, assessed them and extracted data.

Main results

Six trials were identified. Two trials were excluded since they were not randomised and one old, small trial because it was not possible to assess whether is was randomised. The three included trials comprised 483, 476 and 37 patients, respectively. No data have been published from one of the large trials, but the company stated in a press release that the trial failed to confirm the results from an earlier study and that further clinical development was suspended. In the other large trial, relative risk for chronic infection was 0.91 (95% confidence interval 0.55 to 1.49), and in the small trial, the risk was also close to one. In the large trial, one patient was reported to have died in the observation period. In that trial, 227 adverse events (4 severe) were registered in the vaccine group and 91 (1 severe) in the control group. There was a marked rise in flagella antibody titres in the vaccine group and no change in the placebo group (P < 0.0001).

Authors' conclusions

Vaccines against Pseudomonas aeruginosa cannot be recommended.

摘要

背景

以疫苗預防肺纖維囊腫(cystic fibrosis)患者之綠膿桿菌(Pseudomonas aeruginosa)感染

慢性肺部感染在肺纖維囊腫患者身上造成日益加重肺部傷害。一旦綠膿桿菌在肺部形成菌落,便幾乎不可能根除。以減少綠膿桿菌感染為目的的疫苗已研發出來。

目標

評估疫苗在肺纖維囊腫患者預防綠膿桿菌感染的效果。

搜尋策略

我們以疫苗和綠膿桿菌(vaccines AND pseudomonas)為關鍵字搜尋Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register資料庫(最新搜尋日期為2008年5月),以及用疫苗和肺纖維囊腫(vaccin* AND cystic fibrosis)為關鍵字搜尋PubMed資料庫(最新搜尋日期為2008年5月)。

選擇標準

針對肺纖維囊腫患者進行綠膿桿菌疫苗(口服、針劑或鼻噴霧型)與對照組之疫苗或不作任何處置之比較的已發表或未發表的隨機試驗(randomised trials)。

資料收集與分析

2位作者獨立地選取試驗,進行評估及摘錄數據。

主要結論

搜尋結果得到6分文獻。2份因為不是隨機試驗而被排除,1份較舊較小規模研究的文獻因無法評估是否為隨機試驗而排除。剩下被收納的3份文獻分別包含了483、476和37位患者。其中1份大規模研究文獻尚未發表,無法取得可用數據。另1份大規模研究文獻中,慢性感染的相對風險(relative risk;RR)為0.91(95% CI 0.55 to 1.49)。剩下的小規模研究文獻中,風險的值也接近1。在大規模研究文獻中,1位患者在觀察期間死亡,實驗組中登錄了227個副作用事件(4個嚴重事件),對照組中登錄了91個副作用事件(1個嚴重事件)。鞭毛抗體力價(flagella antibody titre)在疫苗組有顯著上升而在安慰沒有變化(P < 0.0001)。

作者結論

無法推薦使用疫苗預防綠膿桿菌感染。

翻譯人

本摘要由臺灣大學附設醫院郭百曾翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

肺纖維囊腫是遺傳疾病,患者肺部會製造濃稠黏液。綠膿桿菌及其他細菌會引起肺部長期感染,結果造成永久性肺部傷害。以減少綠膿桿菌感染為目的的疫苗已被研發出來,而了解這些疫苗是否能預防感染是重要的。我們搜尋相關隨機對照試驗(randomised controlled trials)並收納了3份文獻,分別包含了483、476和37位病人。其中1份未發表的大規模研究文獻無法取得可用數據,剩下的另1份大規模研究文獻及1份小規模研究文獻中,得到慢性感染的風險沒有減少。在大規模研究文獻中,1位患者在觀察期間死亡,實驗組登錄了227個副作用事件(4個嚴重事件),對照組登錄了91個副作用事件(1個嚴重事件)。我們無法推薦使用疫苗預防綠膿桿菌感染。

Résumé scientifique

Vaccins pour la prévention de l'infection par la Pseudomonas aeruginosa dans les cas de mucoviscidose

Contexte

En cas de mucoviscidose, l'infection pulmonaire chronique entraine une dégradation progressive des poumons. À partir du moment où la colonisation des poumons par la Pseudomonas aeruginosa s'est produite, elle est presque impossible à éradiquer. Des vaccins ont été développés dans le but de réduire l'infection par la Pseudomonas aeruginosa.

Objectifs

Évaluer l'efficacité de la vaccination contre la Pseudomonas aeruginosa dans les cas de mucoviscidose.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais cliniques du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques, à l'aide des termes 'vaccines AND pseudomonas' (dernière recherche 19 avril 2011), ainsi que dans PubMed à l'aide des termes 'vaccin* AND cystic fibrosis' (dernière recherche le 25 mai 2011).

Critères de sélection

Des essais randomisés (publiés ou non) comparant des vaccins (oraux, parentéraux ou intranasaux) contre la Pseudomonas aeruginosa à des vaccins de contrôle ou à l'absence d'intervention dans les cas de mucoviscidose.

Recueil et analyse des données

Les auteurs ont sélectionné les essais, évalué leur qualité et extrait les données de manière indépendante.

Résultats principaux

Six essais avaient été identifiés. Deux essais ont été exclus parce qu'ils n'avaient pas été randomisés et un petit essai ancien parce qu'il n'était pas possible de vérifier s'il avait été randomisé. Les trois essais inclus comprenaient respectivement 483, 476 et 37 patients. Un des grands essais n'avait abouti à la publication d'aucune donnée, mais la compagnie avait déclaré dans un communiqué de presse que l'essai n'avait pas confirmé les résultats d'une étude antérieure et que le développement clinique était suspendu. Dans l'autre grand essai le risque relatif d'infection chronique était de 0,91 (intervalle de confiance à 95 % 0,55 à 1,49), et dans le petit essai le risque était également proche de 1. Dans le grand essai, le décès d'un patient avait été signalé durant la période d'observation. Dans cet essai, 227 événements indésirables (dont 4 graves) avaient été enregistrés dans le groupe du vaccin et 91 (dont 1 grave) dans le groupe témoin. Il y avait eu une hausse marquée des titres d'anticorps flagellés dans le groupe à vaccin et aucun changement dans le groupe à placebo (P <0,0001).

Conclusions des auteurs

Il n'est pas possible de recommander les vaccins contre la Pseudomonas aeruginosa.

Абстракт

Вакцины для профилактики инфекции, вызванной синегнойной палочкой (Pseudomonas aeruginosa), при муковисцидозе

Введение и актуальность

Хроническая легочная инфекция при муковисцидозе приводит к прогрессирующему повреждению легких. После того, как произошла колонизации легких синегнойной палочкой (Pseudomonas aeruginosa) , провести ее эрадикацию (выведение из организма) практически невозможно. Вакцины, направленные на снижение инфекций, вызванных синегнойной палочкой (Pseudomonas aeruginosa), разработаны.

Задачи

Оценить эффективность вакцинации против синегнойной палочки (Pseudomonas aeruginosa) при муковисцидозе.

Методы поиска

Мы провели поиск в регистре испытаний Кокрейновской группы по муковисцидозу и генетическим расстройствам, используя термины "vaccines AND pseudomonas" (вакцины и псевдомонада) (последний поиск 30 мая 2013 года) и в PubMed, используя термины "vaccin* AND cystic fibrosis" (вакцина и муковисцидоз) (последний поиск 30 мая 2013 года).

Критерии отбора

Рандомизированные испытания (опубликованные или неопубликованные), сравнивающие вакцины синегнойной палочки (Pseudomonas aeruginosa) (пероральные, парентеральные или интраназальные) с контрольными вакцинами или отсутствием вмешательства при муковисцидозе.

Сбор и анализ данных

Авторы независимо отобрали испытания, оценили их и извлекли данные.

Основные результаты

Было идентифицировано шесть испытаний. Два испытания были исключены, так как они не были рандомизированными, а также одно старое небольшое испытание, так как было невозможно оценить, являлось ли оно рандомизированным. В трех включенных испытаниях состояло 483, 476 и 37 пациентов, соответственно. Не было опубликованных данных одного из крупных испытаний, но компания заявила в пресс-релизе, что испытание не смогло подтвердить результаты более раннего исследования, и что дальнейшая клиническая разработка была приостановлена. В другом крупном испытании, относительный риск хронической инфекции составил 0,91 (95% доверительный интервал от 0,55 до 1,49), и в небольшом испытании риск был также близок к единице. В крупном испытании сообщали, что один пациент умер в период наблюдения. В этом испытании было зарегистрировано 227 неблагоприятных событий (4 тяжелых) в группе вакцины и 91 (1 тяжелое) в контрольной группе. Были отмечены значительный рост титров жгутиковых антител в группе вакцины и отсутствие изменений в группе плацебо (р <0,0001).

Выводы авторов

Вакцины против синегнойной палочки (Pseudomonas aeruginosa) не могут быть рекомендованы.

Plain language summary

Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis

Cystic fibrosis is a hereditary disease where thick mucus is produced in the lungs. Pseudomonas aeruginosa and other bacteria cause long-lasting lung infections which result in permanent lung damage. Vaccines aimed at reducing infection with Pseudomonas aeruginosa have been developed, and it is important to know whether vaccination can prevent lung infection. We searched for randomised controlled trials and included three trials with 483, 476 and 37 patients respectively. No data are available from one of the large trials, which is unpublished. In the other large trial and in the small trial, the risk of getting a chronic infection was not decreased. In the large trial, one patient was reported to have died in the observation period. In that trial, 227 adverse events (four severe) were registered in the vaccine group and 91 (one severe) in the control group. We cannot recommend the use of vaccines against Pseudomonas aeruginosa.

Résumé simplifié

Vaccins pour la prévention de l'infection par la Pseudomonas aeruginosa dans les cas de mucoviscidose

La mucoviscidose est une maladie héréditaire dans laquelle un mucus épais est secrété dans les poumons. La Pseudomonas aeruginosa et d'autres bactéries sont responsables d'infections pulmonaires durables qui causent des dommages irréversibles aux poumons. Des vaccins visant à réduire l'infection par la Pseudomonas aeruginosa ont été développés et il est important de savoir si la vaccination est capable de prévenir l'infection du poumon. Nous avons recherché des essais contrôlés randomisés et avons inclus trois essais impliquant respectivement 483, 476 et 37 patients. Aucune donnée n'était disponible pour l'un des grands essais, qui n'avait pas été publié. Dans l'autre grand essai et dans le petit essai, le risque de contracter une infection chronique n'avait pas diminué. Dans le grand essai, le décès d'un patient avait été signalé durant la période d'observation. Dans cet essai, 227 événements indésirables (dont quatre graves) avaient été enregistrés dans le groupe du vaccin et 91 (dont un grave) dans le groupe témoin. Nous ne pouvons pas recommander l'utilisation de vaccins contre la Pseudomonas aeruginosa.

Notes de traduction

Traduit par: French Cochrane Centre 22nd February, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Резюме на простом языке

Вакцины для профилактики инфекции, вызванной синегнойной палочкой (Pseudomonas aeruginosa), при муковисцидозе

Муковисцидоз является наследственным заболеванием, при котором в легких вырабатывается густая мокрота. Синегнойная палочка (Pseudomonas aeruginosa) и другие бактерии вызывают продолжительные легочные инфекции, которые приводят к необратимому повреждению легких. Вакцины, направленные на снижение инфекций, вызванных синегнойной палочкой, были разработаны, и важно узнать, может ли вакцинация предотвратить инфекцию легких. Мы провели поиск рандомизированных контролируемых испытаний и включили три испытания с 483, 476 и 37 пациентами соответственно. Не было доступа к данным одного из крупных испытаний, которое не было опубликовано. В другом крупном испытании и в небольшом испытании риск приобретения хронической инфекции не уменьшился. В крупном испытании сообщали, что в период наблюдения один пациент умер. В этом испытании, 227 неблагоприятных событий (четыре тяжелых) было зарегистрировано в группе вакцины и 91 (одно тяжелое) в контрольной группе. Мы не можем рекомендовать использование вакцин против синегнойной палочки (Pseudomonas aeruginosa) .

Заметки по переводу

Перевод: Юдина Екатерина Викторовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

Background

Description of the condition

Cystic fibrosis (CF) is an autosomal recessive genetic disease in Caucasians affecting approximately 1 in 2500 to 4700 live births (Lewis 1995). The gene that is abnormal encodes a protein called the cystic fibrosis transmembrane regulator protein (CFTR) which is a membrane bound chloride channel important in the transport of salt and water in and out of the cells that line the airways (Sheppard 1995). This in turn leads to the production of thick mucus, which causes plugging of the airways and impairs the clearance of bacteria from the lungs (Döring 1995). Recurrent episodes of infection and inflammation lead to progressive damage to the lung tissue, characterised by bronchiolitis and bronchiectasis and eventually to respiratory failure.

Recurrent and chronic lung infections are caused by Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa (P. aeruginosa) and in some patients with CF also Burkholderia cepacia complex (Høiby 2000). Virtually all patients with CF will eventually become infected with P. aeruginosa. The presence of P. aeruginosa is associated with a pronounced antibody response and a marked neutrophil inflammation (intense acute inflammation), which is ineffective in clearing the bacteria from the lungs (Sheppard 1995). The main reasons are that P. aeruginosa produces alginate (carbohydrate), which surrounds the bacteria growing in small colonies within the lungs (biofilm). This biofilm mode of growth protects the bacteria from the host defence mechanisms and antibiotics (Høiby 1995).

The immune response can be divided into the antibody-mediated response, and the cellular-mediated response. When bacteria infect the airways, an antibody response usually ensues in immunocompetent individuals. As a result, antibodies which can hinder the attachment of further bacteria and neutralise toxic products are produced. Additionally, the antibodies activate the complement system, and increase the ability of some white blood cells, neutrophil leukocytes, to ingest and kill bacteria. Most patients with CF produce large quantities of antibodies directed against various components of P. aeruginosa. However, the naturally occurring immune response is generally ineffective in clearing the infection, and the antibodies may even be detrimental, e.g. because of immune complex formation. Wheeler and colleagues (Wheeler 1994) found that CF children with low antibody levels (total IgG) had better respiratory status than those with a normal or high IgG level. The ability of antibodies to fight infection is limited, as neutrophil elastase and other enzymes digest them. P. aeruginosa also produce large quantities of alginate that may mask targets for antibodies on the surface of the bacteria. Additionally, P. aeruginosa growing in microcolonies are too large to be ingested and killed by neutrophils, which allows the bacteria to effectively evade the immune system. The constant attempts of the immune system to clear the large microcolonies of P. aeruginosa results in leakage of toxic enzymes from neutrophils (frustrated phagocytosis), causing further lung damage (Döring 1995; Sheppard 1995).

Description of the intervention

Vaccination aims to elicit a long-term protective immune response by the administration of a safe preparation of an organism or a purified or recombinant component. Vaccination may be effective:

  1. by preventing an organism entering the body (usually by generation of neutralising antibodies);

  2. by eliciting a strong immune response that clears infection rapidly, should it occur; or

  3. by neutralising toxic products of the infecting organism during the course of the infection.

Once an immune response has been induced, it cannot be readily reversed, even if it subsequently proves to be detrimental.

How the intervention might work

The role of the cellular immune system involving T lymphocytes and their products in protection against bacterial infections is unclear in patients with CF. However, in a rat model of chronic P. aeruginosa lung infection, a vaccine containing depolymerised alginate conjugated to toxin A produced a cellular response (Th1 response) that was protective (Johansen 1995). It is possible, although by no means clear, that such a response could be beneficial in CF.

It has generally been accepted that the immune function is normal in patients with CF. However, it has been demonstrated that the CF gene product, CFTR, is expressed on T lymphocytes, and that production of chemical messengers that co-ordinate the immune response (cytokines) by these T lymphocytes may be altered in CF (Moss 1996). Thus, the response to vaccination may be altered in patients with CF.

Why it is important to do this review

We aimed to study whether vaccination against P. aeruginosa is beneficial in CF, and to compare the effects of different vaccines. There are two potential groups of patients with CF in whom vaccination against P. aeruginosa is of interest:

  1. patients who are not yet colonised by P. aeruginosa;

  2. patients who are intermittently colonised by P. aeruginosa.

Objectives

To study the immunogenicity and clinical effectiveness of vaccination against P. aeruginosa in CF, and to compare the effects of different anti-pseudomonal vaccines. Specifically, we wished to test the following hypotheses that vaccination against P. aeruginosa:

  1. delays or prevents chronic P. aeruginosa lung infection;

  2. prevents deterioration in respiratory function;

  3. decreases the frequency of pulmonary exacerbations;

  4. increases the levels of anti-pseudomonas antibodies in serum or secretions;

  5. enhances T cell reactivity to P. aeruginosa.

Methods

Criteria for considering studies for this review

Types of studies

Randomised trials, in any language, published or unpublished.

Types of participants

Patients with CF, diagnosed on the basis of abnormal sweat test or genotype, or both, of all ages and degrees of disease severity, regardless of the P. aeruginosa colonisation status.

Types of interventions

Experimental intervention: vaccination with oral, parenteral or intranasal P. aeruginosa vaccines.
Control interventions: placebo, no intervention, other vaccines, or different schedules or doses of the same vaccine as in the experimental group.

Types of outcome measures

Clinical and laboratory outcomes were considered for the review. Changes in certain laboratory outcomes may demonstrate that a vaccine provokes an immune response. However, this does not necessarily imply a protection, since immune responses to vaccines can also be neutral (providing neither protection nor damage) or harmful.

We defined chronic infection as either presence of P. aeruginosa in the lungs for at least six months, based on at least three positive cultures with at least one month intervals with direct (e.g. inflammation or fever) or indirect (specific antibody response) signs of infection and tissue damage; or a positive antibody response in at least two examinations for participants who do not expectorate and present negative bacterial cultures (Döring 2000; Döring 2004).

Primary outcomes
  1. Time to chronic P. aeruginosa infection

  2. Pulmonary function

    1. forced expiratory volume in one second (FEV1) as per cent of predicted for age, sex and height

    2. forced vital capacity (FVC) as per cent of predicted for age, sex and height

  3. Mortality

Secondary outcomes
  1. Frequency of infective pulmonary exacerbations (per patient-year)

  2. Days of antibiotic usage (per patient-year)

  3. Body mass index (BMI)

  4. Shwachman score (a score which includes clinical and x-ray measures of disease severity)

  5. Days unable to carry out normal daily activities (days per patient-year)

  6. Adverse events

  7. Antibody levels to P. aeruginosa in serum, saliva or bronchoalveolar lavage (BAL)

  8. T cell proliferation to P. aeruginosa antigens in cells recovered from serum, sputum or BAL

  9. T cell cytokine production in response to P. aeruginosa antigens in cells recovered from serum, sputum or BAL

Search methods for identification of studies

Electronic searches

Relevant trials were identified from the Group's Cystic Fibrosis Trials register using the terms: vaccines AND pseudomonas.

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching through the abstract books of two major cystic fibrosis conferences - the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module. Date of last search: 30 May 2013.

We also searched PubMed (see Appendix 1). Date of last search: 30 May 2013.

Searching other resources

The register held by the Cochrane Vaccine Field (comprising handsearching of Vaccine and the Journal of Medical Virology) was also searched; reference lists of identified papers were checked; and research institutes and companies involved in the development or marketing of relevant vaccines were contacted.

We accepted letters, abstracts and unpublished trials.

Data collection and analysis

For each step below, we resolved any disagreements by discussion.

Selection of studies

The two authors independently selected the trials to be included in the review.

Data extraction and management

The two authors independently extracted data using a data collection form.

Assessment of risk of bias in included studies

The two authors independently assessed the risk of bias. In particular, we recorded generation of the randomisation sequence, concealment of treatment allocation, any blinding, and exclusions of patients from the analysis.

Measures of treatment effect

We sought data on on all randomised patients, i.e. including patients the investigators might have excluded because of poor compliance, ineligibility or loss to follow-up (intention-to-treat analysis).

For dichotomous data, we used the risk ratio. For continuous outcomes, we preferred post-treatment values when available rather than changes. For time-to-event data, we preferred to use the hazard ratio, but accepted the relative risk if that was the only statistic available.

Dealing with missing data

When trial reports provided insufficient information, we contacted the corresponding author.

Assessment of heterogeneity

If there are enough trials in future updates of this review, we will assess statistical heterogeneity visually and by use of the I2 statistic (Higgins 2003).

Assessment of reporting biases

We accepted letters, abstracts and unpublished trials in an attempt to minimize the impact of publication bias. In future updates of this review, we will attempt to assess publication bias using a funnel plot.

We also attempt to identify any outcome reporting bias.

Data synthesis

If it should be possible to perform meta-analyses in the future, we will calculate the weighted mean difference or standardised mean difference, as appropriate, for continuous outcomes. We plan to use a random-effects model, as the vaccines will be different.

Subgroup analysis and investigation of heterogeneity

We will try to explain any heterogeneity by comparing the characteristics of participants, interventions and outcomes measured in the included trials.

Sensitivity analysis

If possible in future, we will perform a sensitivity analysis where only trials with adequate allocation concealment are included (Schulz 1995).

Results

Description of studies

Results of the search

We identified six trials and excluded three of these (Day 1984; Gibbs 1970; Lang 2004a).

Included studies

A total of 996 patients had been randomised into one of the three included trials: 483 patients (Döring 2007); 476 patients (Lang 2004b); and 37 patients (Langford 1983). The mean age at enrolment was 7.5 years in one trial (Döring 2007) and 7 years in another trial (Langford 1983); the mean age was not reported in the third trial (Lang 2004b). In all cases, the patients were free of P. aeruginosa at enrolment.

The experimental intervention was a vaccine consisting of flagella proteins of subtypes a0a1a2 and b from strains 1210 and 5142, respectively, that had showed a protective effect in animal studies (Döring 2007), and a polysaccharide vaccine of 16 international serotypes of P. aeruginosa (Lot PEV01, Wellcome) (Langford 1983). Details of the vaccine were not reported in the third trial other than reference to it by its commercial name (Aerugen) (Lang 2004b). The control group received placebo (Döring 2007; Lang 2004b) or no intervention (Langford 1983).

The follow up in one trial was two years (Döring 2007); it was not stated in the second trial (Lang 2004b); and follow up was 10 to 12 years in the third trial (Langford 1983).

For further details, please see the table Characteristics of included studies.

Excluded studies

Three trials were excluded; two trials were not randomised (Gibbs 1970; Lang 2004a) and it was not possible to assess whether the third was randomised, as it is old and has only been published as an abstract (Day 1984). This trial included only 21 children and did not report any clinical outcomes.

Risk of bias in included studies

Allocation

In one of the large trials, the allocation was described as randomised (random numbers algorithm of Wichmann and Hill) and appeared to have been adequately concealed (Döring 2007). The second large trial was described as randomised, but we have no details of the generation or concealment of the allocation sequence (Lang 2004b). Two conference abstracts stated that the small trial was randomised, which one of the investigators has confirmed (Hiller 2005), but we have no details of the randomisation process and regard the allocation concealment as unclear (Langford 1983).

Blinding

In one of the large trials, the treatments were blinded; the placebo contained the same ingredients as the intervention, apart from the vaccine, but there was no information about appearance (Döring 2007). The other large trial was stated to be double-blind, with no further information (Lang 2004b). The small trial was not blinded as it compared vaccination with no intervention (Langford 1983).

Incomplete outcome data

In one of the large trials, intention-to-treat analyses were performed (Döring 2007). In the smaller trial, it is unclear whether the analysis was by intention-to-treat, and reported numbers are inconsistent (Langford 1983). Most reports describe 34 patients, with 17 in each group, but the most recent report describes 37 patients, with 16 and 18 in the analysis.

Selective reporting

There is very little information about one of the large trials and most of it comes from slides presented at congresses (Lang 2004b). It was stated in a press release that the trial failed to confirm the results in an earlier study and that the company had suspended further clinical development (Lang 2004b).

Other potential sources of bias

In the Döring trial, the authors noted that there were no significant differences between the groups in sex, age, height, weight, body mass index and FEV1 at baseline (Döring 2007). However, as there were rather obvious differences in a table, we checked this statement. There were no data for body mass index, but we calculated significant differences for age (P = 0.01), height (P = 0.008) and weight (P = 0.04), with higher numbers in the vaccine group. Differences of such magnitudes do occasionally happen in adequately randomised trials, e.g. in 8 out of 1000 trials, if height is considered, and they are not necessarily important, but as the statement in the paper was incorrect, it raises the question whether other analyses were also incorrectly reported.

In the small trial, the patients were "divided into two groups, matched for age and sex" "with no knowledge of clinical details" (Langford 1983). However, "several patients allocated to a group developed pseudomonas infection after the study commenced but before they could be entered and vaccinated", and the authors reported that "this led to some slight imbalance in sex distribution" despite the matching for sex. This suggests that some patients (no numbers are given in any of the publications) with a poor prognosis who were allocated to the vaccine group were either excluded from the trial or later changed status and were referred to the control group.

Effects of interventions

As noted above, data were available for only one of the large trials, involving 483 patients (Döring 2007), and for the small trial of 37 patients (Langford 1983). We have only included outcomes for which we have been able to obtain data.

Primary outcomes

1. Time to chronic P. aeruginosa infection

Kaplan-Maier plots or hazard ratios were not available. In the large trial, it is reported that the risk ratio for chronic infection was 0.91 (95% confidence interval (CI) 0.55 to 1.49) (Döring 2007).

In the small trial, 6 out of 17 of the vaccinated patients had become chronically infected compared to 7 out of 17 of the controls after three years; and nine patients in both groups after seven years (Langford 1983). After 10 to 12 years follow up, 6 out of 10 surviving patients in the vaccine group and 7 out of 12 in the control group were infected.

2. Pulmonary function
a. FEV1 as per cent of predicted for age, sex and height

FEV1 was measured in the large trial, but no data were provided, only a statement that there was no difference between the groups in the rate of decline during the trial period (Döring 2007). In the smaller trial, in theP. aeruginosa infected subgroup, FEV1 was 50% of predicted in the vaccinees and 57% in the control group. After 10 to 12 years the mean FEV1 was 62% of predicted for the 10 vaccine group survivors, and 58% of predicted for the 12 controls (Langford 1983).

b. FVC as per cent of predicted for age, sex and height

After 10 to 12 years the mean FVC in the small trial was 73% of predicted for the 10 vaccine group survivors, and 69% of predicted for the 12 controls (Langford 1983).

3. Mortality

In the large trial, one patient died from acute lymphatic leukaemia (described in an adverse effects table) (Döring 2007). In the small trial, one patient had died in each group after seven to eight years follow up (Langford 1983). After 10 to 12 years, six patients in each group had died, at a median age of 17 years in both groups. All those who died were chronically infected with P. aeruginosa.

Secondary outcomes

4. Shwachman score

This outcome was not measured in the large trial (Döring 2007). In the small trial, the one to three years follow-up data showed no significant difference in Shwachman score with a mean score of 71 (range 36 to 92) in the vaccinees and 73 (range 51 to 90) in the controls (Langford 1983). At seven years of follow-up, the authors stated that the two groups had similar scores. The P. aeruginosa infected vaccinees demonstrated a mean fall in Shwachman score from 80 to 58, whereas the controls fell from 80 to 62.

6. Adverse events

In the large trial, 227 adverse events (four severe) were registered in the vaccine group and 91 (one severe) in the control group (Döring 2007). All but one patient recovered. This patient developed acute lymphatic leukaemia, which was not considered related to the vaccine, and died. The numbers of patients who had one or more events were not stated. In the small trial, 1 out of 17 vaccinees had a mild local reaction (Langford 1983).

7. Antibody levels to P. aeruginosa in serum, saliva or bronchoalveolar lavage (BAL)

In the large trial, there was a marked rise in flagella antibody titres in the vaccine group and no change in the placebo group (P < 0.0001, reciprocal IgG titres were below 1500 at baseline and increased to about 7000) (Döring 2007). In this trial, the authors' primary outcome was number of patients with at least one positive throat culture or at least one positive antibody titre against antigens not represented in the vaccine, risk ratio 0.80 (95% CI 0.64 to 1.00).

In the small trial, the antibody response to some of the 16 serotypes of P. aeruginosa in the vaccine was measured by an enzyme-linked immunosorbent assay (ELISA) (Langford 1983). Antibody responses were discussed, but no data were provided. The authors noted that vaccination did not produce a protective immune response.

None of the other secondary outcomes were reported.

Discussion

The trial data we reviewed did not suggest that the vaccines tested for preventing infection against P. aeruginosa were effective. Two large trials have been performed, but no data have been made public from one of them (Lang 2004a). The press release announcing that the company had suspended further clinical development stated that the trial failed to confirm the results from an earlier study but did not contain any data (Lang 2004b). We contacted the company and were initially informed that we would be able to obtain the unpublished data. However, we have not received any information, not even when we only asked for an abstract. The press release was distributed in July 2006, and we believe it is an obligation towards the patients who volunteered for the trial that the results of their efforts and altruism become publicly available. Other researchers may develop vaccines and it is important to know about past successes and failures to proceed as rationally as possible.

In the other large trial, the patients were recruited over a three-year period, until February 2000 (Döring 2007). An additional seven years passed before the trial was published in 2007. The analyses could therefore have been more powerful if the authors had used survival analysis and followed the patients up for longer, rather than reporting a relative risk after only two years.

In the small trial, there were no meaningful data on lung function. A significantly larger fall in PEFR was observed in the vaccinated group during follow up, but a significantly higher mean PEFR on entry was also observed (Langford 1983). Furthermore, this was a subgroup result among those 13 out of 34 patients who developed chronic infection, and after ten years, there was no difference in survival, lung function or proportion with chronic P. aeruginosa infection.

Effective vaccines have been developed against other bacteria, e.g. Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae, and there is clearly a need for additional basic research to further increase our understanding of those elements of the immune response to P. aeruginosa that could potentially have a protective effect in patients with CF. Beneficial alterations in immune responses have been seen in animal experiments (Johansen 1995) and should be further evaluated (Moser 2000).

Authors' conclusions

Implications for practice

Vaccines against P. aeruginosa cannot be recommended.

Implications for research

Additional basic research is needed to further increase our understanding of those elements of the immune response to P. aeruginosa that could potentially have a protective effect. The risk of inducing immunologically mediated damage following vaccination must be considered in all trials, and long-term follow up of all trial patients will be necessary to adequately address this issue when new vaccines have been developed.

Acknowledgements

We thank Olwen Beaven and Mandy Bryant for performing the searches for this review, Tracey Remmington and Nikki Jahnke for assisting in the update of this review, Joan E Hiller, Gerd Döring and Christoph Meisner for providing additional information on their trials, and Mary Keogan who was an author on previous versions of the review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. PubMed search strategy

vaccin* AND cystic fibrosis

What's new

DateEventDescription
30 May 2013New search has been performed

A search of the Cochrane Cystic Fibrosis and Genetic Disorders Review Group's Cystic Fibrosis Trials Register did not identify any potentially eligible new studies for this review.

A search in PubMed did not identify any potentially eligible new studies for this review.

30 May 2013New citation required but conclusions have not changedThere are no new studies included at this update of the review and our conclusions have not changed.

History

Protocol first published: Issue 2, 1998
Review first published: Issue 1, 1999

DateEventDescription
25 May 2011New search has been performedA search of the Group's Cystic Fibrosis Trials Register and PubMed did not identify any new references potentially eligible for inclusion in the review.
12 June 2009New search has been performedA search of the Group's Trials Register did not identify any new references eligible for inclusion in this review.
13 August 2008New citation required and conclusions have changedConclusions changed in light of newly included evidence.
13 August 2008New search has been performedIn this update, two more trials were included, with 483 and 476 patients, respectively (Döring 2007; Lang 2004b). In the previous version of the review, only one small trial of 37 patients was included (Langford 1983).
13 August 2008AmendedConverted to new review format. Plain language summary has been updated in line with current guidance from The Cochrane Collaboration.
7 February 2007New search has been performedMinor update
27 February 2006AmendedMary Keogan has ceased to be involved with this review; Helle Krogh Johansen has taken on the role of lead author and Peter C Gøtzsche has joined the review as co-author.
27 February 2006New search has been performedAdditional information has been added to the only included study (Langford 1983); another study (Day 1984) has been moved from the 'Studies awaiting assessment' section to excluded studies.

The search of the Cochrane Cystic Fibrosis (CF) and Genetic Disorders Group's CF trials register found one new reference to a study that was already included in the 'Ongoing studies' section of the review (Döring 2007). This study has now been moved to the 'Studies awaiting assessment' section.

An additional reference to an excluded study (Lang 2004a), which was previously listed as Cryz 1997, has been added.

Information on an ongoing study has been included in the 'Characteristics of ongoing studies' table (Lang 2004b).
16 December 2002AmendedThe section "Types of outcome measures" was re-formatted in line with updated guidelines from the Group's editorial team.
16 December 2002New search has been performedThe search of the Cochrane Cystic Fibrosis (CF) and Genetic Disorders Group's CF trials register found no new trials eligible for inclusion in the review.
19 November 2001New search has been performedMinor update

Contributions of authors

The review was designed by Mary Keogan and Helle Krogh Johansen. Both contributed to critical appraisal of papers and data extraction; MK was lead author and drafted the review and subsequent updates, HKJ commented on the drafts.

As from Issue 1, 2006, MK was no longer involved with the review, and Peter C Gøtzsche became co-author. From this issue, HKJ and PG contributed to appraisal of papers, data extraction and interpretation, and to the writing of the manuscript.

HKJ and PCG are guarantors of the review.

Declarations of interest

None known.

Differences between protocol and review

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Döring 2007

MethodsRandomised 1:1 in blocks of 12 stratified by centre. Double-blinding. Public funding.
Participants483 randomised, all in intention-to-treat analyses, and 381 in per protocol analyses. Method of diagnosis of cystic fibrosis not stated ("conventional criteria"). Age: 1 or 2 years (both limits stated) to 18 years, free of P. aeruginosa. 239 children received vaccine and 244 placebo.
Interventions4 doses of vaccine consisting of pseudomonas flagella proteins of subtypes a0a1a2 and b from strains 1210 and 5142, respectively, every 4 weeks (first 3 doses) and last dose after 1 year, or placebo.
OutcomesPrimary: infection with P. aeruginosa, diagnosed by a positive throat swab or positive antibody titre towards other antigens (exotoxin A, alkaline protease, or elastase) than the flagella proteins in the vaccine.
Another outcome was added during the trial: chronic infection, diagnosed by 3 positive swabs or titres during 1 year.
Other outcomes were: specific antibodies against vaccine components and flagella subtypes; adverse events. FEV1 was measured but no data were provided.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random numbers algorithm of Wichmann and Hill".
Allocation concealment (selection bias)Unclear risk"Syringes numbered with the randomisation code". "Patients...assigned...in ascending numerical order as they were enrolled consecutively".
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo contained same ingredients, apart from vaccine; no information about appearance. Statistical analysis plan finalised before unblinding, and allocation list not provided to statistician until closure of data entry. Statistician independent of company that provided drugs.
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analyses.
Selective reporting (reporting bias)High riskFEV1 was measured but no data were provided. There was a Supervisory Board, but no rules are described for interim analyses or for stopping the trial. Author informed us that the role of the board was to monitor systematic reactions to the vaccine after 48 patients had been treated.
Other biasHigh riskSignificant differences at baseline despite contrasting information in the trial report. One-sided significance level used in power calculation, although it is known that antibodies may be harmful.

Lang 2004b

MethodsRandomised, double-blind.
Participants476 participants.
InterventionsFour doses of polyvalent pseudomonas vaccine (Aerugen Berna Vaccine) or placebo at 0, 2, 12 and 24 months, or placebo.
OutcomesPrimary: prevention of colonisation.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo data available.
Allocation concealment (selection bias)Unclear riskNo data available.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double-blind, but no data available on the method.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo data available.
Selective reporting (reporting bias)High riskNo data are available, and we did not receive any data from the company when we requested them.
Other biasUnclear riskNo data available.

Langford 1983

  1. a

    P. aeruginosa: Pseudomonas aeruginosa

MethodsRandomised after matching for age and sex. No blinding.
Participants37 randomised, 34 in analyses.
Method of diagnosis of cystic fibrosis not stated.
Age: 2 years to 18 years, free of P. aeruginosa.
17 children received vaccine and 17 were not immunised.
InterventionsWellcome polyvalent pseudomonas vaccine (a freeze-dried blended extract of 16 international serotypes of P. aeruginosa). Three initial doses over a 3-month period, followed by yearly booster doses, all given subcutaneously. Dose of 0.25 ml given to those under 12 years and 0.5 ml to those over 12 years. The control group was not treated.
OutcomesTime to P. aeruginosa infection (cultures approximately every 2 months), peak flow, Chrispin-Norman X-ray score and Shwachman score (measured annually). Specific Pseudomonas antibodies were measured (annually) but not reported in detail. Adverse events noted.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not described.
Allocation concealment (selection bias)Unclear riskMethod not described; paper states allocation was performed with no knowledge of clinical details.
Blinding (performance bias and detection bias)
All outcomes
High riskThe control group was not treated.
Incomplete outcome data (attrition bias)
All outcomes
High riskDue to acquisition of pseudomonas infection between recruitment and vaccination in a number of participants in one group, several early values for peak flows were missing reducing the number of participants in whom this outcome could be assessed.
Other biasHigh riskPaper states that "several patients allocated to a group developed pseudomonas infection after the study commenced but before they could be entered and vaccinated", and the authors reported that "this led to some slight imbalance in sex distribution" despite the matching for sex. This suggests that some patients (no numbers are given in any of the publications) with a poor prognosis who were allocated to the vaccine group were either excluded from the trial or later changed status and were referred to the control group.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Day 1984Not possible to assess whether this was a randomised trial as it has only been published as an abstract, in 1984; 10 CF children received a vaccine with 16 components (Wellcome BA 4162), 11 received placebo. No clinical outcomes were reported.
Gibbs 1970Non-randomised study with "blindly-selected controls" where 30 CF children received a heptavalent vaccine of pseudomonas and 30 control CF children received placebo injections. No clinical outcomes were reported.
Lang 2004aNon-randomised study where 26 CF participants received an octavalent-polysaccharide-toxin A conjugate vaccine and a control group of 26 age and sex-matched CF participants was chosen retrospectively.

Ancillary