Kamada (Israel)

In 2023, there were an estimated 10.3 million cases of measles worldwide, a 20% rise compared with 2022, according to data from the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC), largely attributed to insufficient immunization coverage.1 Measles infects up to 90% of nonimmune close contacts2 and may be even more contagious in immunocompromised hosts. Without proven effective antiviral treatment for measles, treatment primarily involves supportive care, and patients have high rates of hospitalization and mortality.2 Measles outbreaks are occurring in regions with high rates of organ and stem cell transplantation, including in North America, Europe, the United Kingdom, India, and others. Many current transplant recipients were born between 1957 and the late 1960s, a cohort at highest risk for poor protection as they are unlikely to have been infected in childhood and may have only had a single dose of heat-killed vaccine, which provided inadequate protection and led to outbreaks of disease. Rates vary but roughly 5%–10% of transplant candidates are measles seronegative prior to organ transplant, rendering a significant subset of transplant recipients vulnerable to measles.3 As live viral measles vaccines cannot safely be administered to immunocompromised adults, the main prevention strategy is administration of immunoglobulins for post-exposure prophylaxis, which the United States Centers for Disease Control recommends for severely immunocompromised individuals within six days of exposure.4 A recent systematic review demonstrated excellent efficacy of immunoglobulin prophylaxis in children ranging from 76% to 100%.5 For those at high risk of exposure in outbreaks or during travel, pre-exposure prophylaxis with immunoglobulins might be efficacious. Variations in anti-measles antibodies titers between different immunoglobulin preparations and batches may impact the effectiveness and durability of protection. Unlike general IVIG, polyvalent hyperimmune globulins are prepared from donated plasma selected for a high antibody titer to a specific infectious agent. Whether measles titers vary in these preparations has not been described. We tested measles IgG antibody titers in different intravenous immunoglobulins (IVIGs) (two batches each of Gamunex C (Grifols), Privigen (CSL Behring), and Intratect (Biotest)) and hyperimmune globulins (eight batches of Cytogam (Kamada), two batches of VariZig (Kamada)) using a commercial quantitative ELISA kit (EIA Measles IgG, TestLine catalog # MEG096 lot# 0100102942), where quantitative titers generally correlate with neutralizing antibody levels. The immuno-enzymatic assay used for measles antibody titer assessment included micro-titer wells coated with measles antigen to which the tested samples or reference standard were added. The antibodies thus captured were detected using a secondary antihuman IgG antibody-HRP conjugate that yielded a colorimetric reaction following the addition of tetramethylbenzidine. All donors were from Europe or the United States. The measles titer in the general IVIGs tested was found to be similar, with only minor variation (% coefficient of variation up to 15%) (Figure 1). No significant difference was observed between Varizig and the IVIGs. Cytogam was found to have two times the measles antibody titer compared with IVIGs (p-value 1.2E-07), a difference that was consistent across all eight batches of Cytogam tested. Given the potential severity of measles in immunocompromised patients, it is important for clinicians to know the best methods of prevention, understanding comparative measles antibody titers in currently available immunoglobulin products, which could impact both efficacy and duration of protection; however, the protective thresholds for anti-measles antibodies in patient serum have not been well described. The increased measles titers noted in Cytogam may be because CMV IgG positive donors are more likely to be older, representing the population that may have had clinical measles, resulting in more robust titers compared with those who were vaccinated; there may be alternate explanations. In conclusion, given the potential severity of a measles outbreak in immunocompromised patients, clinicians should be aware of the potential differences in measles IgG titers in immunoglobulin products used for measles post-exposure prophylaxis. This is especially important given the exceptionally contagious nature of measles, the need for timely therapy, and the potential strain on the immunoglobulin supply chain depending on the scope of the outbreak(s). Studies are needed to better understand optimal practices for post- and pre-exposure prophylaxis as well as how to approach the treatment of the immunocompromised patient with measles. Camille N. Kotton serves as a consultant to Kamada, Biotest, and the United States Centers for Disease Control and Prevention and has received research funds from Kamada. Yonit Tiberman, Tamar Auerbach, Roberto Meidler, and Winston Ally are employees of Kamada.

ABSTRACTWe conducted a clinical trial to assess the safety and putative efficacy of an additional human rabies immune globulin (HRIG; KEDRAB) versus an older product (Comparator, HyperRAB S/D® [Grifols]) and determine whether HRIG interferes with development of endogenous antibodies versus Comparator, when each is given with an active rabies vaccine. This was a prospective, double-blind, single-period, non-inferiority study in which subjects were randomized (1:1) to a single dose (20 IU/kg) of HRIG or Comparator on day 0 and rabies vaccine (RabAvert® [GlaxoSmithKline]; 1 mL of ≥2.5 IU/mL) on days 0, 3, 7, 14, and 28. Anti-rabies antibodies were measured by rapid fluorescent focus inhibition test on day 14, and subjects were followed until day 185. Rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL were considered seroconversion putatively indicative of protection. The non-inferiority criterion was the lower limit of the 90% confidence interval (CI) >–10%, for the between-group difference in the proportion of subjects achieving RVNA ≥0.5 IU/mL. On day 14, 98.3% of 59 subjects in the HRIG group and 100% of 59 in the Comparator group had RVNA ≥0.5 IU/mL (difference between proportions – 1.8%; 90% CI, – 8.2, 3.1; non-inferiority criterion met). One subject in the HRIG group did not meet the seroconversion criteria for anti-rabies antibody, and one subject in the Comparator group showed an anamnestic response, with much higher than expected anti-rabies antibody levels at both baseline and on day 14. Thus, HRIG allows for prophylactic anti-rabies antibody titers and is non-inferior to Comparator, when administered with rabies vaccine.

The goal of this study was to test the hypothesis that alpha 1-adrenoceptor activity plays a key role in the release of adenosine from the ischemic myocardium. In 51 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery, and adenosine release into the local coronary vein was measured by the radioimmunoassay technique following the reduction of perfusion pressure for 20 minutes under alpha 1-, alpha 2-, and beta-adrenoceptor attenuations. Adenosine and lactate concentrations in the coronary arterial and venous blood sampled from the perfused area were determined, as well as fractional shortening. In the untreated condition, adenosine release was significantly (p less than 0.01) increased from 1.7 +/- 0.8 (SEM) to 8.8 +/- 1.3 nmol/100 g/min, 20 minutes after the onset of hypoperfusion (coronary blood flow: 28 +/- 2 ml/100 g/min) following the initial overshoot release. Neither beta- nor alpha 2-adrenoceptor attenuation affected the increase in adenosine release during hypoperfusion except for the slight attenuation of the overshoot release by beta-attenuation. In contrast, intracoronary infusions of prazosin and phentolamine during coronary hypoperfusion markedly attenuated (p less than 0.01) release of adenosine (1.8 +/- 0.7 nmol/100 g/min at 20 minutes). The extents of decreases in fractional shortening and lactate production were comparable between the untreated and alpha 1-adrenoceptor attenuation.(ABSTRACT TRUNCATED AT 250 WORDS)

The antiplatelet effects of aspirin and ticlopidine were studied by a dual-tracer method, using indium-111 labeled platelets and technetium-99m human serum albumin, in a group of 12 patients with suspected ischemic cerebrovascular disease. The magnitude of platelet accumulation at the carotid bifurcation was expressed as the ratio of radioactivity of indium-111 platelets deposited on the vascular wall to those circulating in the blood-pool (PAI, platelet accumulation index), 48 hr after injection of labeled platelets. PAI values were measured before (baseline studies) and after the antithrombotic therapies (aspirin studies: 325 mg bid for 22.3 +/- 1.3 days, ticlopidine studies: 100 mg tid for 21.8 +/- 2.1 days). At the baseline, the mean PAI value at 24 carotid bifurcations in the patient group was 15.7 +/- 15.3% (mean +/- S.D.) compared to -4.3 +/- 9.1 at 24 carotid bifurcations in 12 normal subjects (p less than 0.01). We defined the upper limit for a normal PAI (%) value to be +13.9, namely the mean PAI plus 2 SD for the carotid bifurcation in normal subjects and used this value for semiquantitative analysis. At the baseline, significant elevation of PAI (more than 13.9%; positive scintigram) was observed at 12 of 24 vessels, while 12 other regions were negative (less than 13.9%). In the lesions with positive scintigraphic results at the baseline, the mean PAI (%) value from the baseline, aspirin and ticlopidine studies was 29.5 +/- 7.0, 11.2 +/- 8.5 (p less than 0.01 versus baseline) and 21.4 +/- 21.3 (not significant from baseline), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A retrospective study was performed to elucidate the process of left ventricular aneurysm formation and its influence on left ventricular enlargement based on serial two-dimensional echocardiographic observations from 150 consecutive patients with first acute anterior myocardial infarction. Echocardiograms were available and interpretable through the entire period of observation in 68 patients. Because of early death in 13 patients, echocardiograms of 55 patients, 22 with and 33 without aneurysm, were analyzed from 1 to 28 days after infarction. Patients with aneurysms were separated into two groups with large (group 1, 11 patients) and small aneurysms (group 2, 11 patients) on the basis of ratios of aneurysm to overall left ventricular circumferential length [Lcf-LV(RAO)] and area [Area-LV(RAO)], i.e., Lcf(An/LV)-RAO and Area(An/LV)-RAO, respectively, in the right anterior oblique equivalent view at the time of aneurysm formation, with reference to Forrester's subset. Group 1 consisted of patients with Lcf(An/LV)-RAO of 0.4 or greater or Area(An/LV)RAO of 0.3 or greater while group 2 included patients with Lcf(An/LV)-RAO less than 0.4 or Area(An/LV)-RAO less than 0.3. In the test for time trend in these groups with a one-way analysis of variance, Lcf-LV in RAO equivalent and apical four-chamber views and Area-LV in apical four-chamber view effectively separated group 1 from groups 2 and 3 (without aneurysm) with significance (p less than .005, p less than .01, and p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)