The emergence of virulent and antibiotic-resistant strains of Clostridium difficile over the past 15 years has turned the bacterial infection from a nuisance illness into a major crisis for healthcare systems around the world. A vaccine to help protect vulnerable patients – who tend to be elderly and already sick – could represent a big step forward in dealing with the infection.
The start of a 15,000-patient phase III study by Sanofi Pasteur with its vaccine candidate, ACAM-CDIFF, represents the most advanced test of this approach. Others are in development but at much earlier stages; Pfizer and Valneva are the only companies to have clinical stage projects (see table). With the cost of these infections estimated at more than $3bn a year in the US alone, the clinical and commercial potential of a preventative approach is clear.
Cause and effect
Infection with the C difficile bacterium is now a substantial health risk for patients in hospitals or other long-term care facilities, with major outbreaks reported in the UK and US. Its growing prevalence has led the bacterium to rival even meticillin-resistant Staphylococcus aureus as the most common hospital-acquired infection.
Use of broad-spectrum antibiotics is thought to be a major contributory factor because these disrupt intestinal flora, allowing C difficile spores to cause the disease in the gut. The spores will initially have been ingested by the patient on account of a lapse in a hospital’s sanitary measures, for instance. Another reason for recent outbreaks is the emergence of two C difficile strains that have become resistant to the frontline antibiotic fluoroquinolone.
Although diarrhoea is a classic symptom of the infection, its severity can vary from mild diarrhoea through to life-threatening colitis. This extreme inflammation can cause the colon to shut down completely, sometimes requiring part of the bowel to be removed, other times causing death.
While the bacterium has tended to affect elderly, immunocompromised patients, there are increasing reports of infections in the younger, less sick population. Nevertheless, the Sanofi phase III study focuses on primary prevention in older, at-risk patients, and this is a logical starting point for considering a potential market size.
Sanofi gained its candidate through the acquisition of the UK vaccine specialist Acambis in 2008. ACAM-CDIFF is a bivalent vaccine based on the toxins A and B that accumulate in the gut after C difficile infection and cause illness – in healthy people an antibody response to these toxins prevents or limits symptoms. As such, the vaccine seeks to help vulnerable individuals mount an immune response to the bacteria.
Encouraging levels of antibody generation to both A and B toxins was seen in phase I studies. However, Sanofi has not yet released data from two phase II trials, conducted in patients diagnosed with C difficile-associated diarrhoea and healthy patients at risk from infection. It plans to do this soon, the company confirmed, while revealing the phase III initiation earlier this week.
The results must have been positive. However, questions remain about the longevity of protection the vaccine can convey. These are likely to go unanswered until phase III results emerge, in 2018 at the earliest. The company plans to follow the 15,000 patients for three years, and the study will take about four and a half years to complete.
Analysts at Deutsche Bank believe that the market for such a product could be anything from $500m to $2bn, noting that the key challenge is duration of immunity and any requirement for booster shots.
Sanofi has got a lot further with its candidate than other contenders and if successful should have a clear run at the market for some time.
Valneva – formed earlier this year through the merger of European drug developers Vivalis and Intercell – has a project in the second part of a phase I study. This is a recombinant protein vaccine comprising truncated A and B toxins. The ongoing trial seeks to enrol 80 healthy elderly individuals over 65 years of age, testing two vaccine doses and the need for an adjuvant.
Under a development alliance Intercell set up with Novartis back in 2007, the Swiss pharma giant has certain rights to the project.
Pfizer also has a phase I candidate, a DNA vaccine that should generate results later this year, according to clinicaltrials.gov. The company is testing a three-dose vaccination regimen with three different doses with or without adjuvant in healthy adults aged 50 to 85, in a trial seeking to recruit 192 participants. Pfizer has disclosed few details about this to date.
Australia’s Immuron, meanwhile, hopes to move its preclinical candidate into human studies later this year or early next, after revealing encouraging data generated in mice. The company has developed a dairy-derived polyclonal antibody platform that generates vaccines that can be delivered orally.
Finally ImmBio, which has developed a vaccine technology based on antibody-antigen fusion proteins, announced a programme to establish proof of principle against C difficile in 2010, backed by the UK’s Medical Research Council. The private UK company has not updated on its progress since then, but still lists the bacterium as a target on its website.
It will be some time before Sanofi’s project establishes whether the vaccine approach has legs, although the release of phase II data, when it finally occurs, will be closely watched. With drug-resistant strains becoming an ever-bigger problem, any progress will be welcomed.
|Clostridium difficile vaccines in development|
|Phase I||Clostridium Difficile Vaccine||Valneva (Novartis has option)||Intercell||NCT01296386|
|Preclinical||Clostridium Difficile Vaccine||ImmBio||ImmBio|