Passive Transfer of Respiratory Syncytial Virus (RSV)
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JOURNAL OF VIROLOGY, Oct. 1988, p. 3907-3910 Vol. 62, No. 10 0022-538X/88/103907-04$02.00/0 Copyright © 1988, American Society for Microbiology Passive Transfer of Respiratory Syncytial Virus (RSV) Antiserum Suppresses the Immune Response to the RSV Fusion (F) and Large (G) Glycoproteins Expressed by Recombinant Vaccinia Viruses BRIAN R. MURPHY,'* ROBERT A. OLMSTED,' PETER L. COLLINS,' ROBERT M. CHANOCK,1 AND GREGORY A. PRINCE2 Laboratory of Infectious Diseases, National Institute ofAllergy and Infectious Diseases, Bethesda, Maryland 20892,' and Department ofInternational Health, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 212052 Received 11 January 1988/Accepted 14 June 1988 In young infants who possess maternally derived respiratory syncytial virus (RSV) antibodies, the antibody response to RSV glycoproteins is relatively poor, despite extensive replication of RSV. In the present study, it was found that cotton rat RSV hyperimmune antiserum suppressed the antibody response to the RSV glycoproteins but not the response to vaccinia virus antigens when the antiserum was passively transferred to cotton rats prior to infection with vaccinia recombinant viruses expressing the RSV envelope glycoproteins. The cotton rats which had their immune responses suppressed by passively transferred antibodies were more susceptible to infection with RSV than were animals inoculated with control serum lacking RSV antibodies. Furthermore, many of the immunosuppressed animals infected with the vaccinia recombinant viruses developed RSV glycoprotein antibodies which had abnormally low neutralizing activities. Thus, preexisting serum RSV antibodies had dramatic quantitative and qualitative effects on the immune response to RSV glycoproteins, which may explain, in part, the poor RSV antibody response of young human infants to infection with RSV. Our observations also suggest that immunosuppression by preexisting, passively acquired RSV antibodies may constitute a major obstacle to RSV immunoprophylaxis during early infancy, when immuni- zation is most needed. Respiratory syncytial virus (RSV) infection causes serious 9). We observed in this study that there is a dose-dependent lower respiratory tract disease in infants and children and is suppression of the antibody response to the vaccinia virus- unique among respiratory viruses in that the incidence of expressed RSV F and G glycoproteins by passively trans- serious disease is highest among 2-month-old children (1). ferred RSV immune serum and that the immunosuppressed For this reason, immunization strategies to prevent RSV animals are more susceptible to RSV infection than nonsup- disease will involve immunization of very young infants. pressed animals. Recent studies of the immune response of infants and The design of this experiment involved the following children undergoing primary RSV infection demonstrated steps: (i) passive transfer of 4 ml of RSV hyperimmune that infants of less than 9 months of age produce much less antiserum or normal cotton rat serum by intraperitoneal antibody to both the fusion (F) and large (G) glycoproteins inoculation of 3- to 4-week-old cotton rats (Sigmodon his- than do older infected infants and children (3). Further pidus, each weighing approximately 40 g) on day -1, (ii) analysis of the factors that affect the poor immune response inoculation of 107.0 PFU of vaccinia virus recombinant of the young infants revealed that both immunological im- intradermally (0.1 ml) on day 0, (iii) collection of blood from maturity and immunosuppression mediated by maternally animals on days 0, 28, 56, and 91 for quantitation of the RSV derived antibodies played roles (2). The effect of maternally F and G antibodies by using an enzyme-linked immunosor- transferred RSV antibodies on the antibody response to the bent assay (ELISA) and a plaque reduction neutralization G glycoprotein was seen in infants as late as 6 to 8 months of assay, (iv) challenge of animals intranasally on day 91 with age (2). 105-5 PFU of RSV A2 (0.1 ml), and (v) harvest of lung and In the present study, we examined the effect of passively nasal turbinates on day 95 (i.e., on day 4 of RSV infection) transferred RSV immune serum on the immune response for quantitation of virus replication. The methods for deter- induced by the F and G glycoproteins expressed by vaccinia mining the titer of RSV in lung and nasal turbinates, for virus-RSV recombinants. This system was chosen for two antibodies the measuring neutralizing (60% plaque reduction), reasons. (i) The RSV immune serum should not affect ELISA titers for F and the vaccinia virus thus the levels of and for determining antibody against replication of vector; G glycoproteins have been described elsewhere (6). The expression of RSV F and G glycoproteins in control groups ELISA for vaccinia virus antibodies was as should be comparable to those in animals receiving immune performed described previously (3), except that the antigen was purified serum. (ii) Since vaccinia virus recombinants bearing glyco- vaccinia virus strain WR, used at a concentration of 266 protein genes of paramyxoviruses are being considered as jig/ ml. The cotton rat antiserum was derived from live-virus vaccines for use in humans, their ability to stimu- hyperimmune cotton rats that had been infected and rechal- an immune in the of trans- intranasally late response presence passively tissue culture infective doses of ferred antibodies needs to be evaluated quantitatively (5, 7, lenged twice with 105-5 50% RSV A2. This antiserum had a 60% plaque reduction titer of approximately 1:2,000. * Corresponding author. On day 0, the levels of RSV F and G antibodies in serum 3907 3908 NOTES J. VIROL. (Table 1) achieved in the passively immunized animals which ==0 c 00000 0 0 CC 0e undiluted RSV antiserum were within the physio- 00000 0 0 2 ._CC received D . E logical range observed in infants during the first 2 months of life (4). The half-life of the passively transferred antibodies 0 CC 00~ R Cf) tf) 0 N was 6 days (Table 1, group F). By day 56, the en t_- en 0 CC approximately 0 eN _ ri I_ 0 0 C) 0 titer of passively transferred RSV antibodies had diminished +1 +1 +1 +1 +1 +1 +1 to almost background levels (Table 1, group F), allowing o0 N ON00_ 0 ri -o ._ C) U antibody responses to the vaccinia virus-expressed F and G 4 -4 E glycoproteins to be detected unambiguously. 000 0 .5 as 'IC- 'I 0 -~ 0 e The presence of passively transferred RSV immune serum 0 00 0r1i 1- r 0 0 the F and G U cC 0 suppressed the antibody responses to glycopro- CIner- +1 +1 +1 +1 +1 +1 +1 teins in a dose-dependent manner (Table 1, groups A through 0 .r E). Only 33% of the animals that received the largest amount C) 0o r- WI \I 'I 00 00 CZ N o 0 1- -4 CCm of passive antibody (group A) developed an antibody re- 0; 06 sponse to the F or G glycoprotein, but each animal had a 0*cC 3 C) vigorous response to vaccinia virus antigens. The high titer ._ +1 +1 00 >0 +1 +1 +1 +1 +1 of vaccinia virus antibodies that developed in each experi- 00 C) N 000 O0 0 O0 C 2E mental group suggests that the passively administered RSV .U tr 1. ~. tC,tl tn e immune serum did not interfere with the replication of the 0 0 n0 vaccinia virus recombinants expressing the RSV glycopro- CZ e _- _- < 0 en Oc 0N00 N z CO 0 > _ teins. On day 56, the mean ELISA titers for antibody against .. ._ the F and G glycoproteins of animals in group A were ._ ._ reduced 23- and 16-fold, respectively, compared with those a 00 00 000 D 0. +10to N e _0o C- N C-i C 0 in group G, which received normal serum and in which the CA 6 6 O ;o 0 response to vaccinia virus was not affected. This degree of c- +1 +1 +1 +1 +1 +1 +1 C 0. IU) ^ - blN suppression is equivalent to that observed in young infants 0 N 0 0000 2 -4 -4 .> 2 E r 000o 00o +l +l C OC E 08 U 0.0 W)) en 0 0. 2 o0OC- _.C6 0 0 16 >0 +1 +1 +1 +1 +1 +1 +1 oC ._ CC _) 0D ._ eC '00 It O- 'Ci 0 0 c~ 0 15 gQA* cn Cro 0o o r- (3 / 0 14 o ,c F- 0 r- z: 00- 00 C) > ,o,13 o o ,,oo ALAA . In.. o Q 0 CDCDOO cn CC +1 +1 +1 +1 +1 +l +l 12- 0m 0 CD0 000 u) n o(D ._ AA Co LJ .zO 0xug0,e LA q 0 00 CoQ ,, 10 . I0 0, 00 C. E3 en0000 C1W-i t-Nf 8' 6 6 0 o uu 00 C) +1 +1 +1 +1 +1 +1 +1-i 7 w9~ Immune Serum OCoo N 00F 0) en 00 en N EOb. E 60 = undiluted 2 U. 2 6 - 0)6 00 C~I- 2 oV> 00 N 000^ 00Co I: O~ tl C o e = 1:27 0-ON(.-4 -4 C) cl-ri 1- 4 * = 1:81 00 000-+1 +1 +1CCl-+1 \:+1 0 0 0-1 0+ 1 1 3 4 5 6 7 8 9 10 11 12 13 14 C) eq 5, CC U, W- 000oNI C-i 00 C-i C-ClC- C-i 0 Serum Neutralizing Antibody Titer 0 O - 0 0 6 6 >0 g >0 O CC +1 +1 +1 +1 +1 +1 +1 (Reciprocal LOG2) L-i in 0 2 en 0-400 N 0O Oc FIG.