Among the recommended strategies for preventing measles and its complications in exposed, unvaccinated persons is passive protection by antimeasles containing immune globulin. Human intravenous and intramuscular γ-globulins from different manufacturers were studied for manufacturer-specific variation in measles antibody titers. All γ-globulin samples tested were seropositive for measles antibody. Titer variations were found to be clinically insignificant and thus can be used interchangeably for passive antibody protection against measles.
*Department of Pharmacy Practice, University of Rhode Island, Kingston, RI; †Mayo Vaccine Research Group, ‡Translational Genomics Center, §Department of Biostatistics and ∥Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, MN.
This work was supported by grants from the Public Health Service RO1 AI 33144.
Address correspondence and reprint requests to Gregory A. Poland, MD, Mayo Vaccine Research Group, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN. E-mail: firstname.lastname@example.org.
Measles remains a major international problem for 2 principal reasons: the failure of individuals to receive vaccination and the failure of the vaccine itself. For individuals who have been exposed to measles virus but have not yet been immunized, the Advisory Committee on Immunization Practices recommends the administration of γ-globulin to prevent measles in nonimmune persons within 6 days of exposure.1 γ-Globulin is indicated for susceptible contacts of persons with measles at high risk of complications and/or for those with contraindications to receiving the measles vaccine (>72 hours after exposure), including pregnant women, unvaccinated infants aged less than 12 months, and immunocompromised persons.
The recommendations of the Advisory Committee on Immunization Practices state that measles antibody titer variations can occur among particular lots of γ-globulin products.1 However, there is a paucity of contemporary information regarding these variations in measles antibody titer among the many γ-globulin preparations available.2-4 Therefore, we analyzed the measles antibody titer in different human intravenous (IV) and intramuscular (IM) γ-globulin preparations to determine whether any product- or manufacturer-specific differences exist and, if so, the possible significance for clinical use.
One or more lots of IV and IM immune globulin (IVIG and IMIG) preparations were collected from manufacturers and kept at 2°C to 5°C. All lots, kits, and tests were purchased and performed during a 3 month period. A minimum of 0.1 mL of IVIG or IMIG was requested. Overall, 16 lots from 4 different manufacturers (Alpha Therapeutic Corporation (Los Angeles, CA) (n = 6 IVIG), Baxter Healthcare (Deerfield, IL) (n = 1 IVIG), Bayer Corporation (Research Triangle Park, NC) (n = 7 IVIG), and Michigan Department of Public Health (Lansing, MI) (n = 2 IMIG) were tested. Before testing, IVIG samples were mixed according to the manufacturers' product inserts and diluted to an optimal concentration of 100 mg/dL. The IMIG samples were diluted to a concentration of 165 mg/dL. A technician, who was blinded to manufacturer and lot number, quantified measles antibody levels using a whole virus immunoglobulin G (IgG) measles-specific enzyme-linked immunosorbent assay kit and followed the protocol provided by the kit manufacturer (Wampole Laboratories, Cranbury, NJ). Assays were automated and performed in batch fashion on a Wellprep 2000 (BioWhittaker, Walkersville, MD) instrument. A single calibrator set together with positive and negative controls was used to generate a standard plot for titer comparisons. The optical density of the wells was measured at 450 nm on a Thermomax (Molecular Devices, Sunnyvale, CA) microplate reader, and the final values were computed from standard plots using SOFTmax Microplate Reader (Molecular Devices, Menlo Park, CA) software. The manufacturer specified an index value of greater than or equal to 1.1 immune status ratio (ISR) (0.16 IU/mL) as positive, less than or equal to 0.9 ISR (0.12 IU/mL) as negative, and between 0.91 and 1.09 ISR (0.121-0.158 IU/mL) as equivocal. The ISR values were derived from optical density readings by using lot-specific factors provided by the kit manufacturer. In our study, in accordance with clinical practice, equivocal results were categorized as negative. Means and corresponding SDs were used to summarize measles titer values, both overall and by manufacturer. We used single-factor analyses of variance (ANOVA) to compare titer values across manufacturers and type of product (IVIG or IMIG). Because of the small sample size of our study, we supplemented these ANOVAs with exact nonparametric Kruskal-Wallis tests.
Sixteen unique γ-globulin preparations across 4 different manufacturers were examined, and all were seropositive for measles antibody. The overall mean ISR value was 3.83, with a corresponding SD of 0.12, resulting in a coefficient of variation equal to 3.1%. Manufacturer-specific mean ISR values (n, SD) were as follows: Alpha, 3.73 (n = 6; SD, 0.11); Baxter, 3.82 (n = 1); Bayer, 3.87 (n = 7; SD, 0.07); Michigan Department of Public Health, 3.99 (n = 2; SD, 0.01) (Table 1). A SD value for Baxter could not be calculated because only 1 ISR replicate was available. Analysis of variance revealed statistically significant differences in mean ISR values across the manufacturers (ANOVA, P value = 0.01; Kruskal-Wallis test, P value = 0.01). The ISRs for the 2 IMIG products (both from the Michigan Department of Public Health) were somewhat higher than those for the IVIG products (P = 0.03 for both ANOVA and Kruskal-Wallis test).
We found statistically significant differences in measles antibody titers across manufacturer-specific γ-globulin preparations. The samples with the least variation and the highest mean ISR were the IMIG products. However, all of the samples tested seropositive for high levels of measles antibody, and the overall coefficient of variation was a relatively small 3.1%. Thus, although statistically significant, no obvious clinical significance exists, given the small differences we found among the γ-globulin products we tested. Our study showed that all the samples we studied were seropositive for high levels of measles antibody, reassuring clinicians that the use of any of these available US products are acceptable. These findings are consistent with those of other studies.5,6
These results are important for 3 reasons: (1) current γ-globulin lots are prepared from persons who are unlikely to have had measles wild virus exposure; (2) previous studies determined significant variation in Parvovirus B19, cytomegalovirus, and hepatitis B IgG titers among manufacturers,7 raising questions of possible similar measles titer variations; and (3) the possibility of measles titer variation has not previously been examined using whole virus IgG enzyme-linked immunosorbent assay as the method of analysis. This method is less labor intensive, less expensive, and has been shown to be equivalent to the standard neutralization assay.8
In summary, although the samples tested demonstrated titer variation, all were seropositive for high levels of measles antibody, and any differences can be considered clinically insignificant. Clinicians may find this information useful in clinical decision making in the care of susceptible patients who are exposed to measles and can be reassured regarding the use of any of these products in postexposure measles prophylaxis.
We thank the participating companies, without whom this study would not be possible. We also thank the Mayo Immunization Clinic and the Olmsted County Public Health Department for donating IMIG samples and Rochester Methodist Hospital for donating IVIG samples. Dave Greymont, RPh, was an essential contributor to the success of this project. The authors thank Carla L. Tentis and Kim S. Zabel for editorial assistance. This work was supported by a grant from the Public Health Service (RO1 AI 33144). All authors declare no financial interest in any of the companies that manufacture or distribute γ-globulin preparations.
1. Watson JC, Hadler SC, Dykewicz CA, et al. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep
2. Mehta NA, Nanvati AN, Jhala HI, et al. Measles antibodies in commercial preparations of gamma globulin. Indian J Med Res
. 1972; 60:670-673.
3. Kurokawa M, Yasuda J. Antibody spectrum in human immunoglobulin preparation in Japan. Dev Biol Stand
4. Lundblad JL, Londeree N, Mitra G. Characterisation of various intravenous immunoglobulin preparations. J Infect
5. Krause I, Wu R, Shere Y, et al. In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin therapy in infectious diseases. Transfus Med
6. Colomar M, Puga I, Lopez M, et al. Neutralization of measles virus infectivity and antibody-dependent cell-mediated cytotoxicity activity against an Epstein-Barr virus-infected cell line by intravenous immunoglobulin G [corrected]. Clin Diagn Lab Immunol
7. Dockrell DH, Poland GA, Jones MF, et al. Variability in parvovirus B19 IgG levels in intravenous immunoglobulin samples. Diagn Microbiol Infect Dis
8. Cohen BJ, Parry RP, Doblas D, et al. Measles immunity testing: comparison of two measles IgG ELISAs with plaque reduction neutralisation assay. J Virol Methods