Propositive follow-up: Long-term immune responses to the 4CMenB and MenACWY vaccines in people living with HIV.

BACKGROUND: People living with HIV have an increased risk of meningococcal disease. The Propositive trial evaluated co-administration of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in people with HIV. The follow-up trial assessed the immunogenicity of these vaccines at 1.5 and 2.5 years after primary vaccination. METHODS: Participants who completed the parent Propositive trial were invited to the follow-up study. Immunogenicity analysis was performed at 18 and 30 months after primary vaccination. Primary outcome measures were serum bactericidal antibody (SBA) geometric mean titres (GMTs) against three MenB reference strains and the proportion of participants maintaining a protective SBA titre of ≥4 at 18 and 30 months. Secondary outcome measures were SBA GMTs against MenA, C, W, and Y serogroups and the proportion of participants maintaining a protective SBA titre of ≥8 at 18 and 30 months. The trial is registered with Clinicaltrials.gov (NCT042394300). RESULTS: A total of 40 participants aged 22-47 years were enrolled. Geometric mean titres waned by 18 and 30 months but remained higher than pre-vaccination for all MenB strains and MenA, C, W, and Y. In total, 75%-85% of participants retained protective SBA titres by 30 months against individual MenB strains, whereas 68.8% of patients retained protective antibody titres against all three MenB strains. Antibodies against MenC waned more rapidly than did those against MenA, W, and Y. The proportion of participants with protective titres against MenC at 30 months was also lower (46.9%) than that with protective titres against MenA (87.5%), W (78.1%), and Y (87.5%). CONCLUSIONS: Immune responses against MenB in our cohort of people living with HIV at 2.5 years of follow-up were reassuring, with 68.8% of participants retaining protection against all three reference strains. However, responses against MenC were lower than those against MenA, W, and Y serogroups.

Meningococcal ACWY conjugate vaccine immunogenicity in adolescents with primary or secondary immune deficiencies, a prospective observational cohort study.

BACKGROUND: Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure. FINDINGS: We enrolled 69 individuals aged 14-18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3-6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15-0.47] and 0.22 [95% CI: 0.10-0.49], respectively). No serious adverse events were reported by study participants. CONCLUSIONS: The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups.

The propositive study: Immunogenicity and safety of a four-component recombinant protein-based vaccine against MenB and a quadrivalent conjugate MenACWY vaccine in people living with HIV.

BACKGROUND: People living with HIV have been shown to have an increased risk of invasive meningococcal disease. In some countries, meningococcal vaccines are now routinely recommended to all people living with HIV, but no study has yet assessed the immunogenicity and safety of a meningococcal serogroup B vaccine or the co-administration of a MenB and MenACWY vaccine in people living with HIV. METHODS: This phase IV open-label clinical trial investigated the immunogenicity and safety of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in a population of people living with HIV. Immunogenicity analysis was performed before vaccination and 1 month after the second doses of 4CMenB and MenACWY. Primary outcome measures were serum bactericidal assay geometric mean titres against three MenB reference strains at baseline and 1 month post vaccination, the proportion of participants achieving a putative protective titre of ≥4, and the proportion of participants with a ≥4-fold rise in titre from baseline. Secondary outcome measures were serum bactericidal assay geometric mean titres against MenA, C, W, and Y reference strains at baseline and 1 month post vaccination, the proportion achieving a putative protective titre of ≥8, and the proportion with a ≥4-fold rise in titre from baseline. Safety outcomes were solicited and unsolicited adverse events in the 7 days following vaccination. The trial was registered with clinicaltrials.gov (NCT03682939). FINDINGS: In total, 55 participants aged 20-45 years were enrolled. All participants (100%; 95% confidence interval [CI] 93-100) achieved putative protective titres for two of the three MenB strains and for MenA, W, and Y. A total of 98% (95% CI 89-100) achieved a protective titre for the third MenB strain and 94% (95% CI 83-99) for MenC. No serious adverse events were reported. INTERPRETATION: 4CMenB and MenACWY were immunogenic and well-tolerated in a population of people living with HIV 1 month after two doses.

Meningococcal Vaccination Rates Among People With a New Diagnosis of HIV Infection in the US.

Importance: In the United States, individuals with HIV infection have been recommended to receive a 2-dose series of the meningococcal A, C, W, Y (MenACWY) vaccine since 2016 owing to their increased risk of meningococcal disease. Objective: To examine uptake and time to receipt of the MenACWY vaccine among people with a new diagnosis of HIV. Design, Setting, and Participants: This cohort study used health insurance data from the US Optum Research Database from January 1, 2016, through March 31, 2018, to retrospectively identify 1208 individuals aged 2 years or older with 1 or more inpatient claim or 2 or more outpatient claims evidencing a new diagnosis of HIV infection and with continuous insurance enrollment for 12 or more months before and 6 or more months after diagnosis. Follow-up was 6 to 33 months. Statistical analysis was conducted from March 7, 2019, to January 5, 2022. Exposure: Receipt of the MenACWY vaccine. Main Outcomes and Measures: The coprimary outcomes were uptake and time to receipt of 1 or more doses of the MenACWY vaccine after a new HIV diagnosis. Secondary outcomes included uptake and time to receipt of 2 or more doses of the MenACWY vaccine. Vaccination uptake and receipt were estimated by Kaplan-Meier analysis; factors associated with receipt of 1 or more doses of the MenACWY vaccine were identified with multivariable Cox proportional hazards regression analysis. Results: Of 1208 individuals eligible for vaccination (1024 male patients [84.8%]; mean [SD] age, 38.8 [12.5] years; 35 [2.9%] Asian; 273 [22.6%] Black; 204 [16.9%] Hispanic; 442 [36.6%] White), 16.3% were estimated to have received a first dose of the MenACWY vaccine in the 2 years after a new HIV diagnosis. Among individuals who received a first dose, at 1 year or more of enrollment after the first dose, 66.2% were estimated to have received a second dose within 1 year of the first dose. Factors statistically significantly associated with uptake of the MenACWY vaccine included receipt of a pneumococcal vaccine (hazard ratio [HR], 23.03; 95% CI, 13.93-38.09), attendance at a well-care visit (HR, 3.67; 95% CI, 1.11-12.12), West or Midwest geographic region (West: HR, 2.24; 95% CI, 1.44-3.47; Midwest: HR, 1.78; 95% CI, 1.16-2.71), and male sex (HR, 2.72; 95% CI, 1.18-6.26), whereas age of 56 years or older was significantly associated with reduced uptake of the MenACWY vaccine (HR, 0.42; 95% CI, 0.18-0.97). Conclusions and Relevance: This cohort study suggests that MenACWY vaccine uptake among people with a new diagnosis of HIV was low, highlighting the need to educate patients and clinicians about the recommendations for conditions such as HIV infection that increase the risk of meningococcal disease among high-risk populations.

Differentiating vaccine reactions from invasive bacterial infections in young infants presenting to the emergency department in the 4CMenB era: a retrospective observational comparison.

BACKGROUND: Differentiating infants with adverse events following immunisation (AEFIs) or invasive bacterial infection (IBI) is a significant clinical challenge. Young infants post vaccination are therefore often admitted to the hospital for parenteral antibiotics to avoid missing rare cases of IBI. METHODS: During a service evaluation project, we conducted a single-centre retrospective observational study of infants with IBI, urinary tract infection (UTI) or AEFI from two previously published cohorts. All patients presented to hospital in Oxfordshire, UK, between 2011 and 2018, spanning the introduction of the capsular group-B meningococcal vaccine (4CMenB) into routine immunisation schedules. Data collection from paper and electronic notes were unblinded. Clinical features, including National Institute for Health and Care Excellence (NICE) 'traffic light' risk of severe illness and laboratory tests performed on presentation, were described, and comparisons made using regression models, adjusting for age and sex. We also compared biochemical results on presentation to those of well infants post vaccination, with and without 4CMenB regimens. RESULTS: The study included 232 infants: 40 with IBI, 97 with probable AEFI, 24 with possible AEFI, 27 with UTI and 44 post vaccination 'well' infants. C-reactive protein (CRP) was the only discriminatory blood marker, with CRP values above 83 mg/L only observed in infants with IBI or UTI. NICE risk stratification was significantly different between groups but still missed cases of IBI, and classification as intermediate risk was non-differential. Fever was more common in probable AEFI cases, while seizures and rashes were equally frequent. Diarrhoea and clinician-reported irritability or rigours were all more common in IBI. CONCLUSIONS: Clinical features on presentation may aid risk stratification but cannot reliably differentiate IBI from AEFI in infants presenting to the emergency department. Blood results are generally unhelpful due to post vaccination inflammatory responses, particularly in children receiving 4CMenB vaccination. Improved biomarkers and clinical prediction tools are required to aid management in febrile infants post vaccination.

Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases.

Eculizumab, a humanized monoclonal antibody to complement C5, is a therapeutic drug for atypical hemolytic-uremic syndrome (aHUS) that inhibits the terminal pathway of complement. Patients on eculizumab therapy may become more susceptible to infection with capsule-forming bacteria, including meningococci. Therefore, meningococcal vaccination is required for patients who are on eculizumab therapy. However, the means to prevent meningococcal infection in infants who cannot be vaccinated with the available meningococcal vaccine have not yet been established internationally. In two infants with aHUS at 4-5 months after birth, prophylactic oral amoxicillin was administered, and meningococcal infection was not detected during the period between the initiation of eculizumab therapy and the administration of meningococcal vaccine. Neither adverse events related to amoxicillin nor thrombotic microangiopathy occurred during the treatment. Thus, oral administration of amoxicillin may be effective for preventing meningococcal infection under treatment with eculizumab in infants who have not received meningococcal vaccination.

EXOGENOUS MENINGOCOCCAL ENDOPHTHALMITIS: A CASE REVIEW.

PURPOSE: We describe a rare case of exogenous endophthalmitis due to Neisseria meningitidis, of which only two have previously been published. METHODS: Retrospective audit of patient's medical notes. PATIENTS: An 82-year-old man from The Royal Victoria Eye and Ear Hospital, a tertiary ophthalmic service in Melbourne, Australia. RESULTS: Found to have exogenous endophthalmitis from a leaking, filtering bleb. CONCLUSION: This seems to be the first case in which a conjunctival swab was diagnostic. These cases demonstrate that it is reasonable to consider meningococcal endophthalmitis in systemically well patients with leaky filtering blebs. Of note for occupational health and safety, prophylaxis is not required for staff contacts treating these patients.

Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis.

Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.

Unusual Neisseria species as a cause of infection in patients taking eculizumab.

BACKGROUND: Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. METHODS: We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. RESULTS: We identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. CONCLUSIONS: Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.

Practical issues in using eculizumab for children with atypical haemolytic uraemic syndrome in the acute phase: A review of four patients.

AIM: Recently eculizumab, a monoclonal antibody to C5, was found to improve the disease course of atypical haemolytic uraemic syndrome (aHUS) and has been recommended as the first line treatment by an international consensus guideline. However, several practical issues in the use of eculizumab for the acute phase of aHUS have yet to be resolved. METHODS: Children who received eculizumab with diagnosis of aHUS between March 2010 and December 2015 at Tokyo Metropolitan Children's Medical Center were enrolled. aHUS was diagnosed according to the haemolytic uraemic syndrome (HUS) criteria after excluding Shiga toxin-inducing Escherichia coli (STEC) -associated HUS and thrombocytopaenic purpura. We retrieved and analyzed data from the electronic medical records at our institution. RESULTS: We reviewed four patients with suspected aHUS. Eculizumab was discontinued in one patient in whom STEC-HUS was later diagnosed. Treatment was continued in the remaining three patients without recurrence. Practical issues included difficulty in diagnosing aHUS, particularly in the acute phase, risk of infection by encapsulated organisms, especially Neisseria meningitis, and infusion reaction. In addition to issues relating to the acute phase, discontinuing eculizumab in stable patients in the chronic phase must be considered. CONCLUSION: Eculizumab, the first line treatment for children with aHUS, is usually effective. However, certain problems associated with its use require caution to be exercised. As clinical information on eculizumab are still very limited, and the rationale for its long-term use has yet to be established, physicians are advised to exercise care when using eculizumab to manage aHUS.

Infections associated with the use of eculizumab: recommendations for prevention and prophylaxis.

PURPOSE OF REVIEW: Eculizumab inhibits complement effector functions and has significantly impacted the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. However, the risks of potentially life-threatening infections, notably with Neisseria spp. in addition to its cost, are major challenges in clinical practice. In this review, we characterize and summarize the infectious complications reported with the use of eculizumab in the context of its typical and expanding indications. RECENT FINDINGS: Use of eculizumab is rapidly extending to the fields of transplantation and neurology. Eculizumab has been primarily associated with an increased risk of meningococcal infections. Immunization against its commonest serotypes (ABCWY) is now possible with the advent of the meningococcal B vaccine. A combined ABCWY vaccine is underway. Preventive strategies against breakthrough Neisseria infections should also include chemoprophylaxis. Less is known about the association of eculizumab with other infections as recently reported. Surrogate markers of complement blockade, notably CH50, and eculizumab efficacy may help in the risk assessment of infection. SUMMARY: Eculizumab has opened new horizons in the treatment of complement-mediated disorders. Prophylactic and immunization strategies against the risk of Nesseria spp. infections are sound and feasible. The use of eculizumab is expanding beyond complement-mediated diseases to transplantation and neurological disorders. Further research is needed to better define and stratify the risk of infection and prevention strategies in patients with the latter indications.

Cardiovascular aspects of experimental meningococcal sepsis in young and older awake piglets: age-related differences.

Severe meningococcal disease is characterized by: a high load of specific endotoxin, capillary leakage and coagulation disorders. We studied the possible age-related differences in global hemodynamic and regional blood flow responses to different dosages (1 and 10 microg/kg body weight) of rough meningococcal endotoxin in young (8 kg) and older piglets (40 kg). Animals were chronically instrumented and studied in the awake state. The response to plasma infusion (30 mL/kg in 30 min) was evaluated after placebo and endotoxin infusion. The clinical picture was similar in all groups. The mortality was 0/8, 3/8,1/8, 4/9 in young-low, young-high, old-low, and old-high dose respectively. Most important findings were that cardiac index (CI) decreased in the young animals after endotoxin infusion, while it was well preserved in the older animals; in the older animals the systemic vascular resistance dropped 20%, while in the younger ones there was no change in resistance. Conductance to the kidneys, intestines, and spleen decreased significantly more in the young animals, while the increase in conductance and flow to the liver was higher in the old animals; subsequent volume loading resulted only partly in a recovery of the hemodynamic parameters, but failed to improve oxygen delivery.

Effect of meningococcal endotoxin in a rabbit model of shock.

Endotoxin in the form of a lipooligosaccharide (LOS) plays a key role in the development of shock in meningococcal sepsis. To examine hemodynamic and biochemical alterations during meningococcal endotoxic shock, we established a rabbit model. Thirty-nine rabbits, weighing 2.5-4.4 kg, were studied. After anesthesia with intramuscular ketamine (20 mg/kg) and xylazine (4 mg/kg), femoral venous and arterial catheters were inserted. Control animals received only saline, while rabbits in each of four additional groups were given LOS in 10-fold increments from 0.1 microgram/kg to 100 microgram/kg. Mean arterial pressure (MAP), heart rate (HR), respirations (RR), temperature (T), urine output, and arterial blood gases (pH, PCO2, PO2, and bicarbonate) were determined at baseline and hourly. Endotoxin levels and TNF levels were measured at 30, 60, 120, 180, 240, 300, and 360 min post-LOS. Survival was recorded. One-way analysis of variance (ANOVA) and the Scheffe procedure, paired samples t-test, two-tailed t-test, and Fisher's exact test were used. Pearson's coefficients were calculated. Animals receiving meningococcal LOS developed tachycardia and compensated metabolic acidosis with an initially normal pH and MAP. With progression of the shock state, the pH decreased and hypotension ensued. Maximal levels of endotoxin were measured 30 min after LOS injection and declined during the ensuing 6 hr. TNF rose from undetectable to markedly elevated levels and peaked at 60-120 min post-LOS. Increasing the amount of injected endotoxin produced more profound degrees of shock until a dose of 10.0 micrograms/kg was reached. There was no correlation between serum TNF at 60 min and survival at 6 hr or 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)