Abstract: 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). 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.

Plain-language summary: The evidence is current to January 2017. We identified six studies with a total of 557 participants. The studies were blinded, placebo-controlled randomised trials that tested how effective the NTHi vaccine is in preventing infections in people over 18 years of age 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 had no significant impact on reducing the number of acute exacerbations experienced by people with COPD. 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 did not differ 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 the 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. 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. 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 mean the results are more likely to be affected by chance. One trial had more participants than the other five trials combined, and it contributed more to the final analysis. There was moderate heterogeneity (the studies showed quite different results) when this study was included in the analysis, especially in numbers of infections. However, the results were consistent and did not change when this study was 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.