We reviewed the evidence about the effect of a non-typeable Haemophilus influenzae (H. influenzae) (NTHi) vaccine in preventing repeated H. influenzae infections in people with chronic obstructive pulmonary disease (COPD) or chronic bronchitis.
People with COPD can often have frequent infections that worsen symptoms of their lung disease, that is increased breathlessness, purulent discharge and decompensating oxygen saturations levels, known as an 'acute exacerbation'. The most common bacteria that causes this is H. influenzae; it can lead to hospitalisation and sometimes death. If these infections can be prevented with a vaccine, people with COPD may have improved outcomes compared to the current practice of treating infections as they arise.
The evidence is current to July 2014. We identified six studies with 557 participants. The studies were blinded, placebo-controlled randomised trials that tested how effective the NTHi vaccine is in preventing infections in people aged over 18 years with COPD or chronic bronchitis. In all six trials, both the vaccine and placebo group were given at least three courses of tablets at regular intervals over a period of three to 12 months. Generally the baseline demographics of participants across the included studies shared similar characteristics (such as diet, lifestyle and living conditions) to other high-income countries. Ages ranged between 40 and 80 years. The studies counted the number of infections the participants experienced, levels of respiratory tract bacteria, deaths, side effects, hospital admissions or treatment with antibiotics.
The NTHi vaccine has no significant impact on reducing the number of infections COPD patients experience. There was no significant difference in mortality rate between the vaccine and placebo groups and the reported deaths in the vaccinated group were not attributed to the vaccine.
The levels of H. influenzae bacteria found in the respiratory tracts of participants was not significantly different between the vaccine and placebo groups. Due to inconsistencies of measurement between the trials, we were not able to compare the studies against one another.
Antibiotics, which can be an indicator of severe infection, were significantly more commonly prescribed in the placebo group. Evidence of hospital admissions showed that there was no difference in the likelihood of being hospitalised in either the vaccine or placebo group. Two trials studying quality of life found that vaccinated participants generally had a better quality of life, but these results were measured differently and so could not be compared.
Adverse effects were not reported nor clearly defined amongst the trials. Five trials reported adverse effects but there was no particular association with either the vaccine or placebo group. Further research is needed to define adverse effects as outcome measures for more definitive analyses regarding vaccine side effects.
Quality of the evidence
The studies were well conducted with moderate risk of bias. The main limitation of this review was the lack of consistency regarding the definitions and outcome measures among the individual studies, which affected the overall synthesis and interpretation of the results. Fewer participants may cause the results to be more likely to be affected by chance. One trial had more participants than the other five combined and it contributed more to the final analysis. There was moderate heterogeneity (the studies show quite different results) when this study was included in the analysis, especially in numbers of infections. However, the results are consistent and do not change if this study is removed from the analysis.
We concluded after reviewing the relevant studies that the H. influenzae vaccine taken orally in people with chronic bronchitis and COPD does not have a significant reduction in the number and severity of acute exacerbations.
Analyses demonstrate that NTHi oral vaccination of patients with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence is mixed and the individual trials that show a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD.
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. COPD 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.
To assess the effectiveness of an oral, whole-cell, non-typeable H. influenzae (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.
We searched the following databases: CENTRAL (2014, Issue 6), MEDLINE (1946 to July week 3, 2014), EMBASE (1974 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014) and Web of Science (1955 to July 2014). We also searched trials registries and contacted authors of trials requesting unpublished data.
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.
Two 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.
We identified six placebo-controlled randomised controlled trials with a total of 557 participants. They 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 regime in all trials consisted of at least three courses of formalin-killed H. influenzae in enteric-coated tablets taken at intervals (for example, 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 by 2.048% (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.84 to 1.12, P value = 0.68). 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 value = 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 placebo.
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 value < 0.0001). There was no significant difference between the groups with regards to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04, P value = 0.97). Adverse events were reported in all six trials with a point estimate 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 value = 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).