Serologic Response to Meningococcal Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) for the Chronic Treatment with the Terminal Complement Inhibitor Eculizumab
Authors: Roeth Alexander , Alashkar Ferras , Herich-Terhuerne Doerte , Elias Johannes , Vogel Ulrich , Duehrsen Ulrich 
Published: November 2019

Abstract
BACKGROUND: Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to N. meningitids infections (0.48 cases per 100-patient years). The two mainstays to reduce the risk of infection are vaccination at least two weeks prior to treatment and antibiotic prophylaxis.
PATIENTS/METHODS: In this retrospective study serologic response was analyzed after vaccination with a meningococcal vaccine in PNH patients (n=32) by measuring serum bactericidal antibody titers with external rabbit complement (rSBA) against meningococci serogroups A, C, W and Y. 78.1% of the patients (25/32) received a tetravalent conjugate vaccine, while 6.3% (2/32) received an unconjugated polysaccharide vaccine. In 9.4% (n=3) the type of vaccine administrated was not available. Serologic response was defined by an rSBA titer ≥1:8. In 23 patients the corresponding rSBA titers were available. 39.1% (9/23) had been vaccinated more than once due to chronic eculizumab treatment.
RESULTS: Overall serologic responses independent of the time of observation for the meningococcal serogroups were: A: 78.3%, C: 86.9%, W: 47.8%, Y: 69.6%. rSBA titers varied significantly for the different time points [≤2 months (n=1): A: 100%, C: 100%, W: 100%, Y: 100%; ≤4-<6 months (n=4): A: 75%, C: 100%, W: 75%, Y: 75%; ≥6-<12 months (n=5): A: 60%, C: 40%, W: 0%, Y: 40%; ≥ 12-36 months (n=13): A: 84.6%, C: 100%, W: 53.8%, Y: 76.9%]. In 5 patients (15.6%) rSBA titers against 3 serogroups were <1:8, while 5 other patients (15.6%) had rSBA titers <1:8 against 2 serogroups at the same time. Serologic response after vaccination with an unconjugated vaccine even for the third time (n=1) prior to observation due to chronic therapy was identical to patients who had been vaccinated only once, supporting a non-immunological memory post vaccination with an unconjugated vaccine. No meningococcal infections have been observed in the analyzed cohort of eculizumab treated PNH patients so far.
SUMMARY/CONCLUSIONS: Efficiency of meningococcal vaccines for the different serotypes varies significantly and serological response analyses are very useful. Revaccination with the tetravalent conjugate vaccine (Menveo®) every 3 years is recommended or should be based on the individual response. However, physicians and patients must be vigilant for meningococcal infections at all times. Furthermore, stand-by therapy with ciprofloxacin 750 mg p.o. in case of signs of meningococcal infection and immediate medical evaluation and treatment is recommended. The availability of a novel vaccine covering the B-strain (Bexsero®) may further reduce the risk of an infection.

Disclosures
Roeth: Alexion: Consultancy, Honoraria, Research Funding. Duehrsen:Alexion: Honoraria.