CF patients are advised to comply with the recommended vaccination schedule (diphtheria, tetanus, poliomyelitis, acellular pertussis, Haemophilus influenzae type B, Streptococcus pneumoniae, hepatitis B, rotavirus, measles-mumps-rubella, meningococcus), as well as with hepatitis A and influenza vaccination. Recently SARS-COV-2 pandemic disease confirms prioritization of vaccination programmes in people with CF.
Strategies to prevent CF pathogens such as bacteria of the Burkholderia cepacia complex, Pseudomonas aeruginosa, or Mycobacterium abscessus are also in progress ( Le Moigne V et al, 2016).
As previous observational studies have suggested an adverse outcome in terms of lung function and disease progression in people with CF following infection with Influenza A virus and other viral respiratory tract infections, including enterovirus and Coxsackievirus Bs (Stone VM et al, 2022), annual influenza vaccination is commonly recommended in people with CF. A CVB vaccine, currently undergoing clinical development, prevents infection and CVB-instigated lung damage in a murine model of CF.
Antiviral agents, including the neuraminidase inhibitors zanamivir and oseltamivir, may also have a place in the prevention and treatment of influenza.
Covid-19 and CF
Pandemic SARS-COV-2 confirms prioritization of vaccination programmes in people with CF, as there is also evidence of increased risk for post-transplant patients and in those with advanced lung disease (Mathew HR et al, 2021)
Once colonization of the lungs with Pseudomonas aeruginosa (PA) occurs in CF, it is almost impossible to eradicate, resulting in progressive lung damage. Vaccines versus PA, aimed at reducing infection with PA, have been developed in the past, including LPS exstracts from different serotypes, conjugated or not, antigens derived from flagellum and alginate and outer menbrane proteins (Killough M et al, 2022). Currently no licenced vaccine exist to prevent PA infections. Recently it has been proposed a novel subunit vaccine that targets the P. aeruginosa type III secretion system (T3SS) including s fusion of the novel antigen PaF (Pa Fusion), a fusion of the T3SS needle tip protein, PcrV, and the first of two translocator proteins, PopB. This fusion can activate dendritic cells in vitro and promotes IgG and IgA titers in mice model when administered intranasally (Das S et al, 2021).
Streptococcus Pneumoniae (SP) has been found to be the fourth most common bacterial organism isolated from the sputum of people generally associated with mild respiratory involvement with no cases of invasive pneumococcal disease. Pneumococcal vaccination is recommended. No relevant data are available on epidemiology of S. pneumoniae that is expected could be modified by the early intervention of modulators. A recent prospective, observational study at an Adult Italy CF Center (Milan) from March 2017 to September 2019, including data from 129 patients, has been assessed with the aim to evaluate the prevalence of SP DNA and serotype in adults with CF naive to pneumococcal vaccination. SP was found in 24 subjects (19%) and the most common serotypes were 19F (16%), 4 (6%), and 9VA (3%). Higher FEV1 and non-pseudomonas infection significantly associated with SP on sputum (Gramegna a et al, 2021).
Staphylococcus Aureus and Haemophilus Influenzae
Pulmonary exacerbations in CF are more frequently associated with Staphylococcus aureus (SA), PA and Haemophilus influenzae (HI). No specific vaccines are available for Sa and HI.
The strength of current evidence is insufficient to allow conclusions on the use of the active vaccination to prevent RSV in children with CF (read the topic "Palivizumab for the prevention of RSV infection in children with cystic fibrosis").
- To assess the effectiveness of influenza vaccination particularly on morbidity in the 12 months after vaccination; changes in the rate of progression of lung function, nutritional status, numbers of intravenous antibiotic use, P. aeruginosa colonization or infection and death, adverse effects, clinical variability when comparing different types of vaccines.
- To assess the efficacy of neuraminidase inhibitors for controlling influenza.
- To assess the effectiveness of vaccination against P. aeruginosa in CF and to compare the effects of different vaccines.
- To assess the efficacy of pneumococcal vaccines in reducing morbidity and mortality in people with CF.
What is known
1 CDSR (Dharmaraj P et al, 2014) was performed with the aim to compare any influenza vaccine with a placebo. Two out of four studies enrolling 179 subjects with CF (80% were children aged 1 to 16 years) compared an intranasal applied live vaccine to an intramuscular inactivated vaccine and the other two studies compared a split virus to a subunit vaccine and a virosome to a subunit vaccine (all intramuscular). There were no studies comparing a vaccine to a placebo or a whole virus vaccine to a subunit or split virus vaccine. The total adverse events rate ranged from 24% for the intranasal live vaccine to 43% for the split virus vaccine. None of the events was severe. All studies showed a satisfactory serological antibody response generated from influenza vaccinations. However, this response may not result in protection against influenza infection or lung damage. None of the included studies reported clinical outcome measures, such as its impact on PA infection, lung function, length of hospital stay or nutritional status.
According to current practice CF centers recommmed vaccination for influenza in people with CF on an annual basis.
1 non-RCT (Boikos C et al, 2017) involved 198 patients with CF aged 2-19 with CF. Adverse events following live-attenuated intranasal influenza vaccination were most common 0-6 days after LAIV administration, but they were generally benign and self-limiting. Pulmonary exacerbations did not increase in frequency.
1 CDSR (updated 2015) is available. No randomised or quasi-randomised controlled trials on the efficacy of neuraminidase inhibitors for the treatment of influenza infection in people with CF were included in the analysis.
1 CDSR (Johansen HK et al, 2015)was comphensive of trials comparing PA vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in CF.
Six trials were identified. Two trials were excluded since they were not randomised and one small trial because it was not possible to assess whether it was randomised.
Three trials were evaluated including 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% CI 0.55; 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 were registered in the vaccine group and 91 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). In particular, one study (Doring G et al, 2007) showed that active immunization of patients with CF with a marked rise in flagella antibody titres lowered the risk for initial infection with PA. Although many of these patients may acquire PA infections later in life, delaying the onset of chronic infection with PA should result in longer survival of these patients. However, several adverse events were registered in the vaccine group compared to placebo group. So vaccines against PA cannot be recommended.
A phase III Study RCT (NCT01455675) has been completed in June 2017 in order to evaluate clinical efficacy and safety of avian polyclonal anti-pseudomonas antibodies (IgY) in prevention of recurrence of PA infection in CF patients . Results are not available.
A post-marketing study (NCT00633191) completed in 2012 evaluated th effect of "Anti-pseudomonas IgY" i prepared from eggs of hens that have been vaccinated with PA. Patients with CF who are intermittently infected with PA started to gargle with a solution of "anti-pseudomonas IgY" every night to prevent a new infection. Preliminary results showed that it takes a significantly longer time to get a new infection and that the patients get fewer infections than control patients. Any new opportunistic bacteria or fungi (B. Cepacia, S. Maltophilia, A. Xylosoxidans, atypical Mycobacteria, Aspergillus Fumigatus) was found; the use of antibiotics was greatly diminished; t the lung functions and nutritional conditions were maintained in preventing recurrence of PA infections in the two next years.
Several countries as UK and USA include immunization against pneumococcus as part of the routine immunization schedule for children. Children with chronic diseases have a 1.4- fold increased risk of invasive pneumococcal disease compared to healthy children. 1 CDSR is available (Burgess L et al, 2016). In an Italian study the authors (Giannattasio A et al, 2010) speculate that the low uptake rates of pneumococcal vaccination found in less than 20% of children with CF may be due to a lack of awareness of the severity of pneumococcal disease.
Another study (Esposito S et al, 2016) was performed to evaluate Streptococcus pneumoniae colonization rates of school-age children and adolescents with CF showing that it is more prevalent than previously thought. Pneumococcal conjugate vaccination administered in the first year of life does not reduce the risk of re-colonization in later childhood and adolescence.
As no controlled trials were identified we cannot draw conclusions on the efficacy of routine pneumococcal immunisation in people with CF in reducing morbidity or mortality.
Relatively to issue 1:
There is a need to assess the effectiveness of influenza vaccination on important clinical outcome measures and to define efficacy and safety of different types of influenza vaccines.
Adequately powered, randomised controlled clinical trials have to be performed in order to increase evidence for the effectiveness of these interventions in people with CF.
Caution should be considered for further trials in humans when new vaccines will be developed.
Further epidemiological studies are needed to establish whether pneumococcal vaccines reduce the morbidity and mortality in people with CF. As many countries now include pneumococcal immunisation in their routine childhood vaccination schedule it is unlikely that future randomised controlled trials will be initiated. Longitudinal epidemiological studies may offer the opportunity to evaluate the efficacy of pneumococcal vaccination in reducing morbidity and mortality in people with CF.
In the xet years the impact of HEMT on clinical course of lung disease could modify microbiological sputum of people with CF.