Standard gamma globulin, treated with pepsin and injected intravenously five days after infection, conferred passive protection against rubella on five volunteers. Intravenous injection of gamma globulin is superior to intramuscular injection, because the antibodies enter the bloodstream immediately, and an amount of antibody sufficient for protection can be given. Injection of standard gamma globulin is recommended when gamma globulin hyperimmune to rubella virus is unavailabl

Donath, A.

Koechli, B.

Martin du Pan, R.

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THE JOURNAL OF INFECTIOUS DISEASES • VOL. 126, NO.3' SEPTEMBER 1972© 1972 by the University of Chicago. All rights reserved.NOTESProtection of Nonimmune Volunteers against Rubella by IntravenousAdministration of Normal Human Gamma GlobulinR. Martin du Pan, B. Koechli, and A. Donath From the Faculty of Medicine, University of Geneva,Geneva, SwitzerlandStandard gamma globulin, treated with pepsin and injected intravenously five daysafter infection, conferred passive protection against rubella on five volunteers.Intravenous injection of gamma globulin is superior to intramuscular injection,because the antibodies enter the bloodstream immediately, and an amount ofantibody sufficient for protection can be given. Injection of standard gammaglobulin is recommended when gamma globulin hyperimmune to rubella virusis unavailable.Since the first description of rubella embryopathyby Gregg in 1942 [1], it has been proved beyonddoubt that rubella infection during the first 16weeks of pregnancy is a real danger for the em-bryo [2, 3].Until every susceptible woman of child-bearingage can be protected against rubella by an effec-tive and safe vaccine, passive protection of preg-nant women who have come into contact with thedisease will continue to be desirable.The use of either standard or hyperimmunegamma globulin has been widely proposed since1946, when Aycock and Ingalls [4] gave gammaglobulin from normal human serum to four chil-dren infected with or exposed to rubella; however,reports of the efficacy of intramuscular injectionof gamma globulin have been contradictory [5, 6].After it became possible to administer attenuatedrubella virus intranasally to produce a benign dis-ease, Schiff [7] showed that 20 ml of highly titeredimmune globulin (titer of neutralizing antibody,4,096/0.1 rnl) administered 24 hr after intranasalinfection with attenuated rubella virus protectedfive nonimmune volunteers. In contrast, 20 ml ofnormal gamma globulin administered in the sameway failed to protect four out of six nonimmuneyoung men.Received for publication January 17, 1972, and in re-vised form June 8, 1972.Please address requests for reprints to Dr. R. Martindu Pan, 22, Rue de Candolle, 1205 Geneva, Switzerland.341The poor results obtained by Schiff with im ad-ministration of normal gamma globulin could beexplained by an experiment we did with gammaglobulin labeled with 13 11 [8, 9]. Three children(two to three years of age) and three adults wereinjected deeply in the gluteus muscle with 3-5 rnlof gamma globulin labeled with 1311. The injectedgamma globulin remained at the site of injectionfor a rather long time, and only 5%-20% of theinjected gamma globulin was found in the serumtwo to five days later. On the other hand, 40%of the gamma globulin labeled with 13 11 and in-jected iv remained in the serum of one subject fora week.We have already demonstrated that antibodiesto rubella virus, administered iv as human plasma,persist with measurable titers for up to three weeks[10], as might be expected from established dataon the half-life of homologous gamma globulin inman [11].The risk of inducing serum hepatitis by injec-tion of human plasma [12] led us to use iv injec-tion of gamma globulin in our studies.The preparation of hyperimmune gamma glo-bulin for protection against rubella is very diffi-cult, since it is not possible to boost levels of anti-body by injection of live vaccine into personsalready immune. Furthermore, it is not easy tofind large numbers of persons who are convales-cing from rubella and willing to give blood. There-fore, we decided to use standard gamma globulin,processed to be suitable for iv injection, to obtain342a sufficiently high level of antibodies in the bloodof the recipients to protect them against rubella.ExperimentsGamma globulin. Intravenous gamma globu-lin has already been used on a large scale in Swit-zerland for treatment of patients with agammaglo-bulinemia or with serious bacterial infections [13,14]. It is prepared by pepsin digestion of gammaglobulin dissolved in a solution of glycine(pH 4.0) for 3 hr at 37 C, followed by neutral-ization to pH 7.3 [14, 15]. This method removesmost of the anticomplementary properties of stan-dard gamma globulin. The therapeutic effect inchildren suffering from agammaglobulinemia andin patients with bacterial infections and infectionsof the eyes with herpesvirus was generally good.Gamma globulin can be administered iv in largequantities without causing pain or serious reac-tions, and it is rapidly effective [13, 14].The titers of HAl antibodies to rubella virusin five lots of normal gamma globulin preparedand furnished by the Blood Transfusion Labo-ratory of the Swiss Red Cross at Bern were 1 024. 'In four lots and 2,048 in one lot.. To study the protection against rubella con-ferred by iv gamma globulin, we determined thefollowing: (l) the half-life of gamma globulingiven iv, (2) the titer of HAl antibodies to ru-bella virus in the sera of nonimmune recipientsof iv gamma globulin, (3) protection of non-immune adults by iv injection of standard gammaglobulin.Half-life of gamma globulin injected iv, Twohealthy, young adult volunteers were injected ivwith 30!1Ci of 131I-labeled gamma globulin aftertheir thyroid glands were blocked with a 2%solution of KI. Blood samples were drawn atdifferent time intervals during one week. Afterthe presence of free 131I was ruled out, the bio-logical half-life was determined; it was 7.1 daysin the first person and 8.5 days in the second.These results are normal according to the litera-ture [13].Titer of rubella HAl antibodies in sera. Threenonimmune adults, two females (CB and FB)and one male, (JB) received iv infusions of60, 40, and 60 mI, respectively, of normalgamma globulin diluted in 200 mI of 0.9% NaCl.du Pan, Koechli, and DouathTable 1. Titer of HAl antibodies to rubella virusin sera of recipients of I ml of standard gammaglobulin given iv.RecipientGamma globulin and blood CB JB FBAmount of gammaglobulin injected 60ml 60ml 40 mlTiter of HAl antibodies/ml of gamma globulin 1:2,048 I: 1,024 1: 1,024HAl antibodies in bloodBefore injection 0 0 0After 5 min 1:64 1:32 1:8After 1 day 1:16 1: 16 1:8After 5 days 1: 16 1:8 1:8After 14 days 1:8 <1:8 <1:8Samples of blood were taken at intervals from5 min to two weeks.As can be seen from table 1, iv injection of40 or 60 ml of standard gamma globulin increasedthe level of antibodies in the sera of the recipi-ents sufficiently to protect them against rubella.(It is generally accepted that an HAl antibodytiter of 1:8 is protective.)Protection of nonimmune adults by iv gammaglobulin. To determine whether 30-60 ml ofstandard gamma globulin (titer of rubella HAlantibodies, 1: 1,000) given iv would protectagainst rubella, we chose seven students as vol-unteers who were assumed to be nonimmune onthe basis of a negative history of rubella andabsence of HAl antibody in serum.All received 1 mI of a solution containing 104TCID50 viruses of the attenuated Brown strainintranasally.' Five days later, five of the studentsreceived (iv) 30-60 mI of gamma globulin di-luted in 200 mI of saline. Two students (NB andLT) remained as controls and were isolated.Both controls developed mild rubella 10-14days later; one had postauricular lymphade-nopathy, slight rash and fever, arthralgia, and arise in HAl antibodies to 1: 128, while the otherhad the same symptoms, except for arthralgia.The titer of rubella HAl antibodies increased to1: 1,024 five weeks after inoculation of rubellavirus in the second control subject.1 Supplied by the National Institute of Allergy andInfectious Diseases, National Institutes of HealthBethesda, Md. 'Passive Protection against RubellaTable 2. Serologic evidence of protection against rubella with intravenous gamma globulin.343NB (M) 72 0 +LT (F) 62 0 +FB (M) 70 60MF (M) 75 40TB (F) 63 40AL(F) 68 30RS (F) 65 30Subject(sex)Weight(kg)Dose ofgammaglobulin(ml) Symptoms Titer of HAl antibodiesAfterBefore 24 hr 3 weeks 6 weeks0 0 1:256 1: 1,0240 0 1:128 1:1280 1:6 0 00 0 00 1:8 0 00 1:8 0 00 1:8 0 0Table 2 shows that none of the treated stu-dents had symptoms of rubella or elevated titersof antibodies. Three months later one of the stu-dents was infected by the Brown strain andshowed symptoms of mild disease; he did exhibita primary type of antibody response, anotherproof that he had been protected earlier by thegamma globulin. The titer of HAl antibody torubella virus in his serum increased from <1:8before infection to 1: 128 two weeks later and to1: 1,024 six weeks later.DiscussionTo protect a pregnant woman against rubella,we need to know when she was infected. Rubellavirus may be cultured from pharyngeal secretionsas early as one week before the onset of rash [5].However, it is only two to three days before theonset of rash that the titer of excreted virus isreally high [16]. A second factor to be consid-ered is the number of days that elapse betweeninfection and viremia. Viremia can be detectedin the infected person as early as six days afterinfection [5, 17]. Therefore, if we want to pro-tect the fetus, we probably have only five daysbetween infection and the iv administration ofgamma globulin. The favorable results that weobtained support the theory that it should be pos-sible to protect subjects if viremia is prevented.In practical terms, if a pregnant woman isexposed to rubella, the first step is to determinewhether or not she is immune [3, 17, 18] bytesting her serum for antibodies. It is generallyaccepted that titer of HAl antibodies of 1:8 isenough for protection.If she is not immune, 30-40 ml of suitablytreated, standard gamma globulin should be in-jected as soon as possible. The titer of HAl anti-bodies to rubella virus 10-25 and 42 days laterwill show whether the subject has been protectedfrom infection.References1. Gregg, N. M. Congenital cataract following Ger-man measles in the mother. Trans. Ophthalmol.Soc. Aust. 3:35-46, 1942.2. Angela, G. C., Martinesco, G., Di Nola, F., Zunin,C., Vacca, C. La Rosolia. Minerva Med. 58:4759-4826, 1967.3. Martin, du Pan, R. Quels risques court nne femmeenceinte losque son enfant contacte une rubeole?Medecine et Hygiene 27:620-623, 1969.4. Aycock, W. L., Ingalls, T. H. Maternal diseases asa principle in the epidemiology of congenitalanomalies. Am. J. Med. Sci. 212:366-379, 1946.5. Green, R. H., Balsama, M. R., Gilles, J. P., Krug-man, S., Mitrick, G. S. Studies of the naturalhistory and prevention of rubella. Am. J. Dis.Child. 110:348-365, 1965.6. Brody, J. A., Sever, J. L., Schiff, G. M. Preventionof rubella by gamma globulin during an epi-demic in Barrow, Alaska in 1964. N. Engl. J.Med. 272:127-129, 1965.7. Schiff, G. M. The efficacy of titered lots of im-mune globulin in preventing rubella. Interna-tional symposium on rubella vaccines. London1968. Symposium series on immunobiologicalstandardization, vol. 2, p. 83-94, 1969.8. Martin du Pan, R., Scheidegger, J. J., Wenger, P.,Koechli, B., Roux, J. J. Das Verhalten des intra-muscular, intravenos und per os verabreichtengamma globulin. Blut 5: 104-114, 1959.9. Martin du Pan, R., Wenger, P., Koechli, B., Schei-degger, J. J., Roux, J. Etude du passage de la344gamma globuline marquee a travers Ie placentahumain. Clin. Chim. Acta 4:110-115, 1959.10. Martin du Pan, R. Protection of pregnant womanagainst rubella. Lancet 2:546, 1969.11. Wiener, A. S., Gordon, E. B. Studies on humanserum gamma globulin: I. Half-life and rate ofprotection. J. Lab. Clin. Med. 49:258-262, 1957.12. Cockburn, W. C., Harrington, J. A., Zeitlin, R. A.,Morris D., Camps, F. E. Homologous serumhepatitis and measles prophylaxis. Br. Med. J.2:6-8, 1951.13. Barandun, S. Die gamma-globulin therapie. Bibl.haematol. 17(Suppl.):7-134, 1964.14. Barandun, S., Riva, G., Spengler, G. Immunologicdeficiency diagnosis forms and current treatment.du Pan, Koechli, and DouathBirth defect: Origin. Series National Foundationp. 40-46, 1970.15. Kistler, P., Zahler, P. Probleme bei der Herstellungintravenos verabreichbarer humaner GammaGlobulin Losungen, Pathol. Microbiol. 27: 564-571, 1964.16. Cooper, L. Z., Krugman, S. Clinical manifestationsof postnatal and congenital rubella. Arch. Oph-thalmol. 77:434-439, 1967.17. Schiff, G. M., Sever, J. L. Rubella: recent labora-tory and clinical advances. Progr, Med. Virol.8:30-61, 1966.18. Krugman, S., Ward, R. Demonstration of neutraliz-ing antibody in gamma globulin and reevaluationof the rubella problem. N. Engl. J. Med. 259:16-19, 1958.

Protection of Nonimmune Volunteers against Rubella by Intravenous Administration of Normal Human Gamma Globulin

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