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Review
, 6 (6), CD010010

Haemophilus Influenzae Oral Vaccination for Preventing Acute Exacerbations of Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Affiliations
Review

Haemophilus Influenzae Oral Vaccination for Preventing Acute Exacerbations of Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Edward Teo et al. Cochrane Database Syst Rev.

Abstract

Background: Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. Chronic obstructive pulmonary disease is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non-typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis.

Objectives: To assess the effectiveness of an oral, whole-cell NTHi vaccine in protecting against recurrent episodes of acute exacerbations of chronic bronchitis and COPD in adults. To assess the effectiveness of NTHi vaccine in reducing NTHi colonising the respiratory tract during recurrent episodes of acute exacerbations of COPD.

Search methods: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), CINAHL (1981 to January 2017), LILACS (1985 to January 2017), and Web of Science (1955 to January 2017). We also searched trials registries and contacted authors of trials requesting unpublished data.

Selection criteria: We included randomised controlled trials comparing the effects of an oral monobacterial NTHi vaccine in adults with recurrent acute exacerbations of chronic bronchitis or COPD when there was overt matching of the vaccine and placebo groups on clinical grounds. The selection criteria considered populations aged less than 65 years and those older than 65 years.

Data collection and analysis: Two review authors independently assessed trial quality and extracted data from original records and publications for incidence and severity of bronchitis episodes and carriage rate of NTHi measured in the upper respiratory tract, as well as data relevant to other primary and secondary outcomes.

Main results: We identified six placebo-controlled randomised controlled trials with a total of 557 participants. These trials investigated the efficacy of enteric-coated, killed preparations of H influenzae in populations prone to recurrent acute exacerbations of chronic bronchitis or COPD. The vaccine preparation and immunisation regimen in all trials consisted of at least three courses of formalin-killed H influenzae in enteric-coated tablets taken at intervals (e.g. days 0, 28, and 56). Each course generally consisted of two tablets taken after breakfast over three consecutive days. In all cases the placebo groups took enteric-coated tablets containing glucose. Risk of bias was moderate across the studies, namely due to the lack of information provided about methods and inadequate presentation of results.Meta-analysis of the oral NTHi vaccine showed a small, non-statistically significant reduction in the incidence of acute exacerbations of chronic bronchitis or COPD (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.57 to 1.10; P = 0.16). There was no significant difference in mortality rate between the vaccine and placebo groups (odds ratio (OR) 1.62, 95% CI 0.63 to 4.12; P = 0.31).We were unable to meta-analyse the carriage levels of NTHi in participants as each trial reported this result using different units and tools of measurement. Four trials showed no significant difference in carriage levels, while two trials showed a significant decrease in carriage levels in the vaccinated group compared with the placebo group.Four trials assessed severity of exacerbations measured by requirement for antibiotics. Three of these trials were comparable and when meta-analysed showed a statistically significant 80% increase in antibiotic courses per person in the placebo group (RR 1.81, 95% CI 1.35 to 2.44; P < 0.001). There was no significant difference between the groups with regard to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04; P = 0.97). Adverse events were reported in five trials but were not necessarily related to the vaccine; a point estimate is suggestive that they occurred more frequently in the vaccine group, however this result was not statistically significant (RR 1.43, 95% CI 0.70 to 2.92; P = 0.87). Quality of life was not meta-analysed but was reported in two trials, with results at six months showing an improvement in quality of life in the vaccinated group (scoring at least two points better than placebo).

Authors' conclusions: Analyses demonstrate that NTHi oral vaccination of people with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence was mixed, and the individual trials that showed a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD.

Conflict of interest statement

Edward Teo has no potential conflicts of interest to declare. Kathleen Lockhart has no potential conflicts of interest to declare. Sai Navya Purchuri has no potential conflicts of interest to declare. Jennifer Pushparajah has no potential conflicts of interest to declare. Professor Allan Cripps was involved in the initial animal work and conduct of the four trials in Newcastle, Australia. The commercial product, Bronchostat, which originated from these trials, is no longer commercially available. The commercial companies Auspharm International Ltd and subsequently Cortecs International Ltd have ceased trading and were delisted from the Australian Stock Exchange (ASX) in 1991 and 1998, respectively. Prior to 1996, Professor Cripps acted as a consultant for both Auspharm International Ltd and Cortecs International Ltd. Hunter Immunology Ltd subsequently continued development of the oral whole‐cell vaccine (HI‐164). In 2004, Professor Cripps acquired a small stock holding in the company. In 2011, Hunter Immunology Ltd was acquired by Bioxyne Ltd, and Professor Cripps' shares were transferred to Bioxyne Ltd. Subsequently, in February 2014, Bioxyne Ltd sold to Mariposa Health Ltd the HI‐164 Oral Vaccine project and all associated intellectual property. Should Mariposa Health Ltd successfully commercialise the vaccine, Mariposa Health Ltd has agreed to pay Bioxyne Ltd a royalty of up to 6.5% of gross revenue. Professor Cripps retains a small residual stock holding in Bioxyne Ltd. Professor Cripps has no stock holding in Mariposa Health Ltd. He has not received any honoraria, participated in expert testimony, or received any consultancy fees from either Mariposa Health Ltd or Bioxyne Ltd. Professor Cripps' potential conflicts of interest have been assessed by the Cochrane Funding and Arbitration Panel (reference number 150514/064) and considered of low risk. Mieke L van Driel has no potential conflicts of interest to declare.

Figures

Figure 1
Figure 1
Inclusion of trials flow diagram.
Figure 2
Figure 2
Forest plot of comparison: 1 Primary outcomes, outcome: 1.1 Exacerbations (number of exacerbations/person/year). Refer to Table 4 for Overall rate estimates of acute exacerbations across included studies.
Figure 3
Figure 3
Forest plot of comparison: 1 Primary outcomes, outcome: 1.2 Mortality (deaths during trial period).
Figure 4
Figure 4
Forest plot of comparison: 2 Secondary outcomes, outcome: 2.1 Prescriptions (number of courses/person/year). Refer to Table 5 for Overall rate estimates of antibiotic prescriptions across included studies.
Figure 5
Figure 5
Forest plot of comparison: 2 Secondary outcomes, outcome: 2.3 Adverse events (number of adverse events/person/year). Refer to Table 6 for Overall rate estimates of adverse events across included studies.
Analysis 1.1
Analysis 1.1
Comparison 1 Primary outcomes, Outcome 1 Exacerbations (number of exacerbations/person).
Analysis 1.2
Analysis 1.2
Comparison 1 Primary outcomes, Outcome 2 Mortality (deaths during trial period).
Analysis 2.1
Analysis 2.1
Comparison 2 Secondary outcomes, Outcome 1 Prescriptions (number of courses/person/year).
Analysis 2.2
Analysis 2.2
Comparison 2 Secondary outcomes, Outcome 2 Adverse events (number of adverse events/person).

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