Nontypeable Haemophilus influenzae: pathogenesis and prevention.

In this paper, we describe the ability of nontypeable Haemophilus influenzae (NTHi) to coexist with the human host and the devastating results associated with disruption of the delicate state of balanced pathogenesis, resulting in both acute and chronic respiratory tract infections. It has been seen that the strains of NTHi causing disease show a marked genetic and phenotypic diversity but that changes in the lipooligosaccharide (LOS) and protein size and antigenicity in chronically infected individuals indicate that individual strains of NTHi can remain and adapt themselves to avoid expulsion from their infective niche. The lack of reliance of NTHi on a single mechanism of attachment and its ability to interact with the host with rapid responses to its environment confirmed the success of this organism as both a colonizer and a pathogen. In vitro experiments on cell and organ cultures, combined with otitis media and pulmonary models in chinchillas, rats, and mice, have allowed investigations into individual interactions between NTHi and the mammalian host. The host-organism interaction appears to be a two-way process, with NTHi using cell surface structures to directly interact with the mammalian host and using secreted proteins and LOS to change the mammalian host in order to pave the way for colonization and invasion. Many experiments have also noted that immune system evasion through antigenic variation, secretion of enzymes and epithelial cell invasion allowed NTHi to survive for longer periods despite a specific immune response being mounted to infection. Several outer membrane proteins and LOS derivatives are discussed in relation to their efficacy in preventing pulmonary infections and otitis media in animals. General host responses with respect to age, genetic makeup, and vaccine delivery routes are considered, and a mucosal vaccine strategy is suggested.

Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis.

BACKGROUND: Acute bronchitis leading to ongoing exacerbations is a serious condition predisposed to by viruses, bacteria or environmental factors. It can be fatal. Antibiotic therapy is not particularly useful. An oral Haemophilus influenzae vaccine has been developed. OBJECTIVES: To assess the effects of an oral, monobacterial whole-cell, killed, nontypeable H. influenzae vaccine in protecting against recurrent acute episodes in chronic bronchitis. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to January Week 4 2006), EMBASE (1990 to September 2005) and ISI Current Contents (2004 to May 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of the H. influenzae vaccine on patients with recurrent acute exacerbations of chronic bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Three authors extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable H. influenzae measured in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. The vaccine reduced the incidence of bronchitic episodes at three months after vaccination (rate ratio is 0.69; 95% CI 0.41 to 1.14) and at six months after vaccination (rate ratio 0.82; 95% CI 0.62 to 1.09). If these results been statistically significant, they would have represented a reduction in acute bronchitic attacks for vaccinated individuals of 31% at three months, and 18% at six. The effect had disappeared by nine months. The severity of exacerbations in the treatment group, as measured by requirement to prescribe antibiotics, was likewise reduced by 58% at three months (Peto odds ratio = 0.42; 95% CI 0.16 to 1.13), and by 65% at six months (Peto odds ratio = 0.35; 95% CI 0.16 to 0.75). AUTHORS' CONCLUSIONS: Vaccinating patients with recurrent acute exacerbations of chronic bronchitis in the autumn may reduce the number and severity of exacerbations over the following winter. A large clinical trial is needed.

Haemophilus influenzae oral vaccination against acute bronchitis.

OBJECTIVES: To assess the effects of an oral whole cell nontypeable Haemophilus influenzae (NTHi) vaccine in protecting against recurrent episodes of bronchitis. SEARCH STRATEGY: We searched the Cochrane trials register, MEDLINE, Extramed, ISI Current Contents, Carl Uncover and contacted investigators of the studies. SELECTION CRITERIA: Randomised trials comparing the effects of an oral monobacterial NTHi vaccine on patients with recurrent exacerbations of bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable Haemophilus influenzae in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. Oral vaccination using a monobacterial whole cell killed nontypeable Haemophilus influenzae significantly reduced the incidence of bronchitic episodes at 3 months (Weighted Mean Difference [WMD] 6.694; 95% confidence interval [CI] 6.963 - -6.424; p < 0.01) and 6 months (WMD 4.496; 95% CI 4.664 - -4.327; p < 0.01) following vaccination. The effect diminished by 9 months. The severity of exacerbations in the treatment group was likewise reduced by 58% at 3 months (Peto OR = 0. 42; 95% CI 0.16 1.13), and 65% at 6 months (Peto OR = 0.35; 95% CI 0. 16 0.75) following vaccination. REVIEWER'S CONCLUSIONS: Vaccination, in the autumn, of patients with recurrent exacerbations of bronchitis reduced the number and severity of exacerbations over the winter months. A large clinical trial to assess longer term prognosis needs to be completed.

Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis.

BACKGROUND: Acute bronchitis leading to ongoing exacerbations is a serious condition predisposed to by viruses or bacteria. It can be fatal. Antibiotic therapy has not been particularly useful in clearing bacteria such as nontypeable Haemophilus influenzae (NTHi) because they colonise the upper respiratory tract. An oral NTHi vaccine has been developed to protect against recurrent acute episodes in chronic bronchitis. OBJECTIVES: To assess the effects of an oral whole cell nontypeable Haemophilus influenzae (NTHi) vaccine in protecting against recurrent acute episodes in chronic bronchitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1, 2003); MEDLINE (1966 to 2003); EMBASE (1990 - 2003); Extramed (1994 to 2003); ISI Current Contents (1993 to 2003); Carl Uncover (1988 to 2003) and contacted investigators of the studies. SELECTION CRITERIA: Randomised trials comparing the effects of an oral monobacterial NTHi vaccine on patients with recurrent acute exacerbations of chronic bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Three reviewers extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable Haemophilus influenzae measured in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. Oral vaccination using a monobacterial whole cell killed nontypeable Haemophilus influenzae significantly reduced the incidence of bronchitic episodes at three months after vaccination (Poisson rate ratio 0.666; 95% confidence interval [CI] 0.500, 0.887; p = 0.005) and perhaps at six months after vaccination (Poisson rate ratio 0.831; 95% CI 0.669, 1.031; p = 0.093). The effect had disappeared by nine months. The severity of exacerbations in the treatment group, as measured by requirement to prescribe antibiotics, was likewise reduced by 58% at three months (Peto odds ratio = 0.42; 95% CI 0.16, 1.13), and by 65% at six months (Peto odds ratio = 0.35; 95% CI 0.16, 0.75). REVIEWER'S CONCLUSIONS: Vaccination, in the autumn, of patients with recurrent acute exacerbations of chronic bronchitis reduced the number and severity of exacerbations over the winter months. A large clinical trial to assess longer term prognosis is needed.

Pseudomonas aeruginosa: the potential to immunise against infection.

Pseudomonas aeruginosa remains a serious pathogen for specific cohorts of patients where chronic infection is a poor prognostic indicator, such as those with cystic fibrosis, burn wounds or those who are immunocompromised. Significant disease burden is associated with a diverse spectrum of both nosocomial and community-acquired infections. To date, vaccines against P. aeruginosa have shown limited and often conflicting efficacy data, especially against heterologous strains, which are increasingly identified as co-colonisers of biofilms. While few studies have gone beyond Phase II clinical trials, a particular concern is the ability of P. aeruginosa to evade the immune system while provoking an immune response that contributes to the destructive nature of infection. Therefore, vaccine development needs to focus on preventing attachment and colonisation, as well as preventing conversion to a mucoid phenotype that is characteristic of the chronic condition that promotes pathology.

Kinetics of inflammatory cytokines in the clearance of non-typeable Haemophilus influenzae from the lung.

Levels of the pro-inflammatory cytokines TNF-alpha and IFN-gamma were measured from the time of infection to the time of complete clearance of non-typeable Haemophilus influenzae (NTHi) from the lung in immune and non-immune rats. Mucosal immunization facilitated production of significant levels of TNF-alpha as early as 30 min post-pulmonary challenge with NTHi in immune animals. Following the peak at 2 h, rapid decline of TNF-alpha levels occurred from the alveolar spaces. Levels of TNF-alpha in non-immunized animals increased at a slower rate, peaked at a lower concentration and were slower to decline. The significantly larger number of macrophages seen in the immune animals at 1 h after bacterial challenge could partially account for the higher levels of TNF-alpha. Interferon-gamma was not detected in immune or non-immune rats at any time point before NTHi clearance after pulmonary challenge. Study of the kinetics of TNF-alpha release demonstrates that immunized animals control the release of pro-inflammatory cytokines more effectively than non-immunized animals for enhanced clearance of bacterial infection from the lungs.

Characteristics of the immunological response in the clearance of non-typeable Haemophilus influenzae from the lung.

Clearance of non-typeable Haemophilus influenzae (NTHi) from the respiratory tract was investigated, over time, in immune and non-immune rats. A triphasic pattern characterized the clearance of bacteria from the lungs. Mucosal immunization enhanced bacterial clearance from the lungs in each of the three phases compared with clearance from non-immunized animals. Total clearance of bacteria was observed from lung tissue by 12 h in immune animals and 24 h in non-immune animals. Polymorphonuclear leucocytes not only arrived earlier and initially in greater numbers, but disappeared earlier in immune animals (peaking at 8 h post-challenge), compared with non-immune animals (peaking at 12h post-challenge). Systemically derived and locally produced NTHi-specific IgA and IgG correlated with enhanced bacterial clearance during the secondary phase. This model demonstrates that immunized animals up-regulate and resolve inflammatory responses to pulmonary infection more rapidly than the non-immunized controls.

Vaccines and mucosal immunisation.

The earliest attempts to protect humans against infectious diseases and toxins were by administering foreign substances to mucosal membranes, predominantly by the oral route. In the late 1880s, significant attention was given to the concept of 'local' immunisation, and the discipline of mucosal immunology was born in the early 1900s. However, despite the early enthusiasm, progress has been slow, with few mucosal vaccines being efficacious. The complexities of mucosal immune regulation and the lack of appropriate antigen delivery systems which can access mucosal inductive sites, have remained substantial obstacles. Recent studies demonstrating compartmentalisation of the common mucosal immune system create further challenges for the development of organ-specific vaccines. In the 21st century, our knowledge of mucosal immunoregulatory mechanisms, coupled with new technology for antigen delivery and immunomodulation will provide the necessary know-how to see the development and widespread use of mucosal vaccines for both preventative and therapeutic use.

Programmed inflammatory processes induced by mucosal immunisation.

Inflammation is essential to repair tissue damaged by physical, microbial or allergic mechanisms. Inappropriately zealous responses lead to destructive pathology or chronic disease cycles, whereas ideal outcomes are associated with complete and rapid restoration of tissue structure and function. The establishment of a rodent model investigating the different immune responses to non-typeable Haemophilus influenzae infection in both the lung and the ear indicate an ability to clear bacteria and reduce inflammation following mucosal immunisation. Lung histochemistry, upregulaion of macrophages and polymorphonuclear neutrophils, recruitment of gammadelta(+) and CD8(+) T cells, cytokine levels and depletion studies all support the hypothesis that mucosal immunisation facilitates control of the immune response resulting in enhanced bacterial clearance and programming of inflammation which limits damage and promotes the rapid restoration of structural normality.

Mucosal immunity in the lung and upper airway.

The mucosal surfaces of the lungs and upper airways are common sites for infection. Extensive studies of the mechanisms associated with immune responses in the respiratory tract have found that understanding the system is challenging and involves many complex interactions to prevent and eliminate infection. Immune protection against diseases transmitted through the respiratory tract requires an understanding of the important aspects associated with beneficial, detrimental or ineffective immune responses. Two critical aspects of an immune response against a pathogen are that of the inductive stage, either induced by vaccination or primary infection, and the effector stage, the ability to recognise, respond to and eliminate the infection without detriment to the host. An immunisation strategy must not only have a measure of the induced antigen specific response, but this response must also be protective.

CD8+ T cells have an essential role in pulmonary clearance of nontypeable Haemophilus influenzae following mucosal immunization.

A rodent respiratory experimental model has proved useful for investigating the immune mechanisms responsible for clearance of bacteria from the lungs. Immunohistochemical studies in immune and nonimmune rats have identified the cellular kinetics of response to bacterial pulmonary infection for CD8+, CD4+, and gammadelta+ T cells; B cells; and the expression of major histocompatibility complex class II (MHC-II). During the course of bacterial clearance, there was no apparent proliferation or extravasation of lymphocytes, nor was there increased expression of MHC-II in nonimmune animals despite an influx of polymorphonuclear leukocytes, whereas in immunized animals there was an early influx of CD8+ and gammadelta+ T cells, followed by enhanced expression of the MHC-II marker, cellular infiltration by polymorphonuclear leukocytes, and finally an increased number of CD4+ T cells. Depletion of CD8+ T cells confirmed their vital contribution in the preprimed immune response to pulmonary infection by significantly decreasing the animals' ability to clear bacteria following challenge.