Post-Eculizumab Meningococcal Disease in A Vaccinated Patient

A recent report shows that patients receiving eculizumab remain extremely susceptible to meningococcal disease, including from nongroupable Neisseria meningitidis strains, despite having been vaccinated against the disease.

Deirdre Nolfi-Donegan, MD, from UPMC Children’s Hospital of Pittsburgh, Pennsylvania, and colleagues published the report in the August 2018 issue of Emerging Infectious Diseases, the monthly peer-reviewed public health journal of the US Centers for Disease Control and Prevention (CDC).

“Patients receiving eculizumab have an increased risk for meningococcal disease, but most reported cases are attributable to encapsulated meningococcal strains,” the authors write. “We describe a case in which a nongroupable meningococcal strain, which rarely causes disease in healthy persons, caused fatal disease in an eculizumab recipient despite meningococcal vaccination.”

According to Dr Deirdre Nolfi-Donegan, eculizumab is the only drug with US Food and Drug Administration (FDA) approval for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome.

The mechanism of action of eculizumab involves inhibiting terminal complement-mediated intravascular hemolysis. However, in doing so, it also blocks formation of the membrane attack complex that is used to kill a variety of Gram-negative bacteria, and plays a key role in the body’s defense against N. meningitidis.

As such, prescribing information for eculizumab includes a black box warning for increased risk of meningococcal disease in patients who receive the drug. Nevertheless, data have shown that some patients receiving eculizumab who are up to date with meningococcal vaccination can still develop meningococcal disease.

However, most of these cases have involved encapsulated meningococcal isolates.

In contrast, Dr Nolfi-Donegan and colleagues report a case caused by nongroupable meningococci.

The patient was a 16-year-old girl who was previously healthy but received a diagnosis of PNH after presenting to the hospital with abdominal pain, pancytopenia, and laboratory evidence of hemolysis. In preparation for eculizumab immunotherapy, she received a booster vaccine targeting N. meningitidis serogroups A, C, Y, and W-135, and a 2-dose series of MenB-4C vaccine targeting N. meningitidis serogroup B.

Approximately 6 months after PNH diagnosis, the patient began eculizumab treatment due to worsening symptoms. However, within 48 hours of receiving the second dose of eculizumab, she died of overwhelming N. meningitidis disease.

Using whole-genome sequencing, clinicians isolated a meningococcal strain from the patient’s meninges. It was nongroupable and contained 2 antigens that were 97% (factor H binding protein [FHbp]) and 100% (Neisseria heparin binding antigen [NHba]) identical to the respective antigens present in the MenB-4C vaccine the patient had received.

Additionally, a sample of serum obtained at postmortem examination showed high immunoglobulin G reactivity against these 2 antigens that were expressed by the infecting strain of N. meningitidis.

“Neither prior vaccination with MenB-4C, which matched 2 antigens present in the strain, nor the high serum antibody levels to FHbp and NHba in the patient prevented rapidly fatal disease in the presence of eculizumab,” the authors stress.

In otherwise healthy patients, the most invasive meningococcal disease is caused by encapsulated strains of the bacterium. In contrast, however, unencapsulated strains are often associated with asymptomatic nasopharyngeal carriage. Indeed, the sequence type of the isolate from this case has been seen predominantly among isolates from asymptomatic carriers.

“These breakthrough cases underscore the need for healthcare providers and patients to have a high index of suspicion for meningococcal disease, leading to quick recognition and consideration of early empiric treatment, regardless of the patient’s vaccination status or chemoprophylactic regimen,” Dr Nolfi-Donegan and colleagues conclude.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.