Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections.

Transcription

Hyperimmune globulins in prevention and
treatment of respiratory syncytial virus
infections.
V G Hemming, G A Prince, J R Groothuis and G R Siber
Clin. Microbiol. Rev. 1995, 8(1):22.
These include:
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CLINICAL MICROBIOLOGY REVIEWS, Jan. 1995, p. 22–33
0893-8512/95/$04.0010
Copyright q 1995, American Society for Microbiology
Vol. 8, No. 1
Hyperimmune Globulins in Prevention and Treatment of
Respiratory Syncytial Virus Infections
VAL G. HEMMING,1* GREGORY A. PRINCE,2 JESSIE R. GROOTHUIS,3
AND
GEORGE R. SIBER4
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 208141; Virion
Systems, Inc., Rockville, Maryland2; Department of Pediatrics, University of Colorado School of Medicine, and the
Children’s Hospital, Denver, Colorado3; and Massachusetts Public Health Biologic Laboratories and Division of
Infectious Diseases and Dana-Farber Cancer Institute, Boston, Massachusetts4
This review will discuss the initial recovery, the characterization, the epidemiology, and the impact on human populations of RSV. It will examine evidence from animal and human
studies indicating protective and therapeutic roles for the
parenteral administration of human polyclonal RSV-specific
immunoglobulin G (IgG) antibodies (RSVIG), and perhaps
RSV-specific monoclonal antibodies, for the prevention, amelioration, or treatment of RSV infections. Immunoprophylaxis
provides a new clinical approach to the prevention and perhaps
the treatment of RSV infections in certain high-risk infants
and young children. Finally, studies indicating that neutralizing
anti-RSV IgG antibodies introduced into the airway by inhalation may be an effective alternative to the parenteral injection of RSVIG for the treatment of RSV LRI in infants and
children will be summarized.
INTRODUCTION
Respiratory syncytial virus (RSV) was first recovered from
primates in 1955 (96) and humans in 1956 (21, 22). By 1961, it
was evident that RSV was a frequent and sometimes serious
respiratory pathogen for infants and young children. A formalin-inactivated vaccine was prepared and tested to determine
whether vaccination might protect infants and young children
from RSV lower respiratory tract infections (LRI) (28, 44, 79,
81). The vaccine stimulated a humoral antibody response.
However, some of the youngest vaccine recipients later became
infected with RSV, developed severe bronchiolitis, and required hospitalization. The investigators suggested that humoral antibody in the absence of mucosal immunity permitted
the development of immune complex disease, which in turn
provoked a more severe bronchiolitis. The acceptance of this
hypothesis hampered scientific inquiry into a clearer understanding of the role of humoral immunity in the pathogenesis
of infant RSV pulmonary infections. Subsequent evidence
derived from human (17, 49, 72, 84, 143) and animal (69,
114–116, 119–120, 130) studies indicated that sufficient serum
antibody was safe and, furthermore, protected the lower
respiratory tract, airways and lung parenchyma, from RSV
infection.
RSV: AN HISTORICAL OVERVIEW
Isolation and Characterization
In October 1955, an apparent epizootic of sneezing, coughing, and mucopurulent nasal discharge occurred in a group of
young chimpanzees housed at the Forest Glen facility of the
Walter Reed Army Institute of Research in Washington, D.C.
Investigators (96) cultured nasal secretions from symptomatic
chimpanzees in human liver epithelial cells (Chang) and
recovered a hitherto unrecognized virus which they called the
chimpanzee coryza agent (CCA) and which they showed to be
causally related to the monkeys’ upper respiratory tract infec-
* Corresponding author. Mailing address: Department of Pediatrics,
Uniformed Services University of the Health Sciences, 4301 Jones
Bridge Road, Bethesda, MD 20814. Phone: (301) 295-3391. Fax: (301)
295-3898.
22
INTRODUCTION .........................................................................................................................................................22
RSV: AN HISTORICAL OVERVIEW ........................................................................................................................22
Isolation and Characterization ...............................................................................................................................22
Epidemiology and Clinical Syndromes ..................................................................................................................23
Vaccine Development................................................................................................................................................23
Animal Models of RSV Infection............................................................................................................................24
Phenotypic Variation ................................................................................................................................................24
RSV AND HUMORAL IMMUNITY ..........................................................................................................................24
Evidence from Studies in Humans.........................................................................................................................24
Evidence from Studies in Animals .........................................................................................................................24
STUDIES OF STANDARD IVIG AND RSVIG FOR THE PREVENTION AND TREATMENT OF RSV
INFECTION IN HUMANS..................................................................................................................................25
Standard IVIG...........................................................................................................................................................25
Development of RSVIG ............................................................................................................................................26
RSVIG Studies in Cotton Rats ...............................................................................................................................26
RSVIG Studies in Children .....................................................................................................................................26
TOPICAL OR INHALED HUMAN IG AND RSVIG STUDIES............................................................................28
IVIG Topical Studies in Cotton Rats and Owl Monkeys....................................................................................28
RSVIG Topical Studies in Cotton Rats .................................................................................................................29
RSV AND MONOCLONAL ANTIBODIES ..............................................................................................................30
CONCLUSIONS ...........................................................................................................................................................30
REFERENCES ..............................................................................................................................................................30
VOL. 8, 1995
HYPERIMMUNE GLOBULINS IN PREVENTION OF RSV INFECTIONS
Kravetz et al. (82) and Johnson et al. (76) were able to infect
the upper airways of adult volunteers with RSV despite the
presence of serum RSV NT antibodies at the time of challenge.
In contrast to the high seroprevalence found in adults, surveys
of children showed RSV titers in only 35% of children under 4
years of age and 29% of those between the ages of 4 and 8
years. In retrospect, it is evident that the assays used in these
pioneering studies were not optimally sensitive; however,
further evidence of the high frequency of RSV infections in
infants and children was provided.
Epidemiology and Clinical Syndromes
Other investigations (26, 57, 63, 64, 80, 85, 87, 94, 121)
affirmed the initial observations regarding the epidemiology of
RSV and its importance in human respiratory infections. The
virus caused annual winter RSV epidemics. The resulting
clinical syndromes of infected infants and young children
included mild upper respiratory tract infections but also bronchitis, bronchiolitis, bronchopneumonia, and laryngotracheitis.
These LRI syndromes could be particularly severe in infants
under 6 months of age. Immunity following primary RSV
infection was often insufficient in magnitude or duration to
protect from reinfection in subsequent years. Reinfections
were usually less severe and were more likely limited to the
upper respiratory tract, especially in children older than 2
years. Most young infants with RSV infections had preexisting
maternal antibody (10, 15, 24, 46, 63, 64, 76, 87, 90, 121, 132).
Most humans experience RSV infection by the second year
of life. Annual seasonal epidemics occur in most communities.
When the virus is highly prevalent, most infants, children, and
adults are placed at risk for infection or reinfection. One of the
paradoxes of RSV biology is the failure of primary and repeat
infections to provoke solid or durable immunity, especially of
the upper respiratory tract (9, 50, 61, 72, 97). In addition to
occasional serious infections in healthy infants and children
(83, 85), other groups at risk for complicated RSV infections
include hospitalized premature infants (15, 58, 59), premature
infants discharged home during the RSV season (35, 53),
hospitalized children (58, 129), infants and children with
chronic cardiac (24, 85, 86, 93, 105) or pulmonary (1, 53, 105)
disorders, immune system-compromised children and adults
(20, 37, 38, 40, 60, 65, 73, 127, 133), and the elderly (2).
Vaccine Development
Clearly, RSV was a common and often serious winter lower
respiratory tract pathogen for the very young. The elusive
search for an effective RSV vaccine was initiated. In the early
1960s, a formalin-inactivated vaccine was prepared and tested
in infants (28, 44, 79, 81). The Bernett strain of RSV, previously isolated in human embryonic kidney cultures, was propagated in human embryonic kidney cells and multiply passaged
in vervet monkey kidney cells. Harvests of RSV-infected cells
were clarified by low-speed centrifugation, inactivated with
1:4,000 formalin, concentrated 25-fold by ultracentrifugation,
and further concentrated 4-fold by alum precipitation. This
preparation is known as lot 100. Infants at four sites (two sites
in Washington, D.C., and military-dependent children at Lowry
Air Force Base, Colo., and Fort Ord, Calif.) each received
three intramuscular doses of vaccine at approximately 1-month
intervals. In one Washington, D.C., study site, nonvaccinated
children were observed as controls. In the other Washington,
D.C., site, control infants received a univalent, formalininactivated parainfluenza virus type 1 vaccine. Control infants
in Colorado and California were immunized with a formalininactivated, aqueous trivalent parainfluenza virus vaccine con-
tions. Seed virus prepared from the original CCA isolation
induced infection and similar respiratory symptoms in other
young chimpanzees. CCA failed to induce detectable infections in guinea pigs, mice, rats, or chicken embryos. The
unintentional spread of CCA was observed between infected
and uninfected chimpanzees housed in a common facility. A
laboratory worker also appeared to become infected with CCA
after contact with infected chimpanzees. Random human
serum samples were surveyed by complement fixation (CF)
and virus neutralization for CCA immunity. The assays suggested that some humans (1 of 12 infants and children 6
months to 2 years, 0 of 12 children 3 to 6 years, 0 of 9 children
7 to 9 years, 2 of 12 children 10 to 14 years, 3 of 13 children 15
to 18 years, and 8 of 40 persons older than 18 years) had been
infected in the past with CCA or a related virus (96).
Shortly after the recovery of CCA, Chanock and colleagues
(21, 22) isolated a CCA-like virus from an infant with bronchopneumonia (Long agent) and another from an infant with
bronchiolitis (Snyder). Serologically and phenotypically, as
characterized by the viruses’ cytopathic effect on cells in
culture and by their neutralization by anti-CCA animal sera,
the Long and Snyder agents appeared to be the same as CCA.
Particularly striking was their ability to induce syncytia and
multinucleated giant cells in Chang liver epithelial cells and
KB cell cultures. It was suggested that respiratory syncytial
virus might be a more suitable name than CCA. CF and RSV
neutralization tests (NT) performed on convalescent-phase
sera from infants with LRI were compared with those done on
sera from uninfected age-matched controls. Test results indicated that many infants and children developed humoral
immunity to RSV during the 5 months of the study. By 3 to 4
years of age, the majority of children studied (77 to 80%)
possessed serum NT antibody (21).
These observations were confirmed by Beem and colleagues
(11), who cultured the upper respiratory tracts and tested sera
from inpatient and outpatient infants and children with respiratory infections during the winter of 1959 to 1960 in Chicago,
Ill. Two CCA-like agents which caused extensive syncytium
formation and the development of multinucleated giant cells in
HEp-2 cells were isolated. Over a 5-month period, similar
agents were recovered from 41 other patients mostly with LRI.
Thirty-one isolations were from children under 2 years of age,
most of whom were less than 6 months old. Convalescentphase sera from the infected infants exhibited poor CF and/or
NT responses to infection, whereas most older children
showed significant antibody responses. Though a variety of
clinical disease patterns were observed, the most common were
bronchiolitis and bronchopneumonia.
Prospective efforts (23, 108) to recover RSV from young
patients in Washington, D.C., began in 1959. The first RSV
isolation occurred in March 1960 during an epidemic of
bronchiolitis. Subsequently, RSV was recovered from 57% of
young infants with bronchiolitis or pneumonia during a
5-month period. RSV was also recovered from older children
with bronchopneumonia and bronchiolitis. The frequent recovery suggested that RSV was an important human respiratory pathogen of early life. Serological data confirmed a high
prevalence of RSV. Its epidemiology was different from those
of influenza viruses A and B and parainfluenza virus types 1
and 3. Serious illness with RSV was most likely to result with
the first infection, especially if it occurred in the early months
of life. Reinfection appeared to be common but usually
induced less severe illness in normal children. This appeared to
explain why older children with nosocomial RSV infections,
who usually were experiencing recurrence, became less ill than
infants with primary infection.
23
24
HEMMING ET AL.
Animal Models of RSV Infection
Models of RSV infection in animals have contributed important information to the understanding of RSV pathogenesis
and immunity. Cotton rats (Sigmodon hispidus) and small
primates such as the owl monkey (Aotus trivirgatus) have been
particularly valuable. Data from animal experiments have
provided important information for use in vaccine development (13, 51, 78, 100, 102, 103, 110, 118–120, 122, 123, 130,
136, 148, 152).
Contrary to expectations posited by the hypothesis suggesting that RSV antibody is harmful, passively immunized, RSVinfected animals such as cotton rats failed to demonstrate that
passively acquired antibody led to enhanced disease. Indeed,
the converse was observed. Passive antibody in sufficient titer
prevented RSV LRI and also could be used to treat RSVinfected animals and reduce RSV titers in infected lung (52,
56, 111, 119, 130).
Phenotypic Variation
Phenotypic and serological variability was noted among
RSV strains shortly after the original isolation and characterization (29, 30, 74, 151). With the biochemical characterization
of the structure of RSV (31, 39) and the advent of monoclonal
antibody technology (7, 8, 32), it became possible to characterize RSV strains (7, 41, 45, 47, 48, 77, 99). Grouping was
based on substantial genetic heterogeneity (19, 33, 77, 131),
especially involving the G glycoprotein, a protein putatively
responsible for RSV attachment to cells. Antigenic variability
of RSV strains and its possible role in explaining the phenomenon of reinfection (95, 96, 139, 144, 147), apparent differences
in disease severity (62, 88, 89, 98), and RSV epidemiology (4,
126, 128, 137) are under investigation.
RSV AND HUMORAL IMMUNITY
Evidence from Studies in Humans
Chanock et al. (23) and Beem (9) observed that young
infants with RSV infections had NT titers to RSV at the time
of infection. Some had ‘‘relatively high’’ titers and yet experienced bronchiolitis or bronchopneumonia. Beem reported that
five of seven infants with documented repeat RSV infection
had serum NT activity at the time of reinfection. RSV antibodies appeared to be poorly protective. It was also uncertain
whether reinfections resulted from antigenic differences between infecting strains.
In 1976, Lamprecht and coworkers (84) observed that,
although maternally derived RSV NT antibodies did not
prevent RSV infection in infants, the severity of RSV pneumonia correlated inversely with the level of NT antibody. This
was not true with regard to the severity of bronchiolitis. In
1977, Bruhn and Yeager (17) reported no correlation among
CF titers in cord blood, acute sera, or convalescent sera in 41
RSV-infected infants. An infant’s ability to respond with a
fourfold rise in antibody titer after RSV infection appeared
related to the amount of passively transferred maternal antibody. Infants under 2 months of age were relatively spared
from infection, indirectly suggesting that antibody might be
protective rather than harmful. Henderson and coworkers (72)
reported a 10-year longitudinal study of respiratory infections
in a small group of healthy children monitored from birth.
During RSV epidemics, primary infection rates of these children exceeded 90%. The rate for second infections was
reduced and that for third infections was reduced further.
Infections induced NT responses but did not provide long-term
protection in all children. Amelioration of illness severity
resulted from successive RSV infections.
Similar observations were made by Ogilvie et al. (106) and
Ward et al. (143), who prospectively studied 100 newborns for
evidence of RSV infection. Maternal antenatal sera were also
examined for anti-RSV IgG by immunofluorescence and by
radioimmunoprecipitation analysis. Twenty-nine of the infants
developed RSV infection. The mean titer of maternal antibody
in mothers whose infants remained uninfected was significantly
higher than that of the mothers whose babies had proven RSV
infection before 6 months of age. Glezen et al. corroborated
these observations (49, 50). They observed that NT titers in
cord sera of 68 infants with culture-proven RSV infection were
significantly lower than those of 575 randomly selected cord
samples of infants born during the same period. During
prospective studies of primary RSV infections and reinfections
in children observed from birth to 36 months of age, more than
three-quarters of the infants and children experienced RSV
infection in the first 2 years of life. Reinfection was common.
The risk of reinfection correlated with the serum neutralizing
antibody titer from the prior RSV infection and with the
number of prior RSV infections.
Evidence from Studies in Animals
In 1975, Prince immunized pregnant female ferrets (111,
119) with live RSV prepared in HEp-2 cells. Infants born to
RSV-inoculated mothers were challenged with RSV shortly
after birth. Rather than experiencing enhanced disease, the
neonatal ferrets were protected from RSV infection by transferred maternal immunity, and protection correlated inversely
with the NT titers in their mothers’ sera (130).
taining types 1, 2, and 3. Serological studies of the vaccinees
verified immune responses by increases in CF and NT antibody
titers. When RSV appeared in the winter season following
immunization, vaccinees were poorly protected from infection.
RSV-exposed vaccinees became infected at the same rate as
controls, and many experienced severe enough bronchiolitis to
require hospitalization. Two deaths occurred in RSV-infected
vaccinees. Formalin-inactivated RSV vaccine not only failed to
protect children from RSV infection but appeared to induce an
exaggerated, altered clinical response to naturally occurring
infection (28, 44, 79, 81). To explain the unexpected outcome
of the trial, it was proposed that vaccine-induced RSV serum
antibody (and similarly, transplacentally acquired maternal
antibody in nonvaccinated infants under 6 months of age), in
the absence of local or mucosal RSV immunity, promoted an
immunologic reaction that was responsible for severe pulmonary disease (25, 27). Similarities between the untoward outcome of the formalin-inactivated RSV vaccine trials and the
complications observed in some recipients of a formalininactivated measles vaccine were noted. Both vaccines were
prepared by the same manufacturer in a similar fashion, i.e.,
grown in simian kidney cells, formalin inactivated, and alum
precipitated. An important difference in outcome between the
two vaccine trials was noted. The measles-immunized children
were initially protected from measles infection and then later
became susceptible and, with infection, developed an altered
disease state known as atypical measles (42, 43, 104).
The fact that natural infection confers a measure of protection against severe repeat RSV infection justifies the continued
efforts to develop vaccines (12, 14, 16, 18, 75, 91, 102, 107, 120,
138, 140–142, 145, 146, 149, 150). To date, the immune responses of infants and young children, immunized with investigational live or subunit vaccines, have provided neither
sufficient nor durable protection.
CLIN. MICROBIOL. REV.
VOL. 8, 1995
25
TABLE 1. Effect of passive immunotherapy on amount of virus present in the nose and lungs of owl monkeys 5 and 7 days postinfectiona
Virus titer (log10 PFU/ml)
5 days postinfection
Treatment
(n)
Lung
None (8) 3.42 6 0.22
IVIG (12) 3.02 6 0.18b
7 days postinfection
No. (%)
of monkeys without
detectable virus
Nose
No. (%)
of monkeys without
detectable virus
Lung
No. (%)
of monkeys without
detectable virus
Nose
No. (%)
of monkeys without
detectable virus
0 (0)
0 (0)
3.37 6 0.31
3.67 6 0.22b
0 (0)
0 (0)
3.20 6 0.37
1.48 6 0.73c
0 (0)
9 (75)
3.32 6 0.40
2.10 6 0.33d
1 (13)
5 (42)
a
Titers are expressed as geometric means 6 standard errors. Significance was determined by comparison with untreated monkeys on the same day. Reprinted from
reference 69 with permission of the publisher.
b
P . 0.05, not significant.
c
P , 0.001, significant.
d
P , 0.05, significant.
immunized animals developed pulmonary inflammatory lesions within 24 h which peaked in severity 4 days after
infection. The examination of microscopic sections of involved
lungs revealed lesions that resembled pulmonary Arthus reactions (neutrophilic infiltration) at 24 h and lymphocytic peribronchiolitis at 96 h. Control animals similarly immunized with
doses of heat-killed RSV demonstrated no pulmonary abnormalities. These findings suggest that the inflammatory response represents an artifact of formalin inactivation of RSV
(117). These observations became extraordinarily important
when we proposed to use exogenous human polyclonal antibodies for the prevention or treatment of RSV infections in
humans.
The success of IVIG prophylaxis and therapy in cotton rats
prompted our testing of the safety and efficacy of IVIG for the
treatment of RSV infections in primates. Adult owl monkeys
were inoculated intratracheally with RSV (69). Bronchoalveolar lavage and nasal swabs were performed every other day
from the 3rd to the 14th infection day in each monkey.
Quantitative RSV cultures were performed on each swab and
bronchoalveolar lavage specimen. On the fifth infection day, 12
animals were infused intravenously with a high-titered lot of
IVIG. Eight other infected, but untreated monkeys served as
controls (Table 1). IVIG treatment on the fifth day of infection
(3,000 mg/kg of body weight given in three divided doses over
24 h) resulted in a mean (approximate) 30-fold reduction (P ,
0.001) in virus from bronchoalveolar lavage fluid. There was
complete clearance of RSV from bronchoalveolar lavage fluid
in 9 of the 12 monkeys 48 h after treatment. RSV was also
significantly reduced in the noses of the monkeys (69).
STUDIES OF STANDARD IVIG AND RSVIG FOR THE
PREVENTION AND TREATMENT OF RSV
INFECTION IN HUMANS
Standard IVIG
The previously cited antibody data and the observations in
cotton rats and owl monkeys prompted an examination of
parenteral infusion of IVIG for the treatment or prophylaxis of
RSV infections in young children. It appeared that standard
commercial IVIG lots might be screened by RSV NT testing
and high-titered lots could be selected for use in the immunologic mediation of RSV infections in children. Lots were
screened and a high-titered lot of Sandoglobulin was identified. This screened lot was used (2,000 mg/kg given over 24 h)
in a blinded, placebo-controlled trial to treat infants and young
children hospitalized with RSV disease (71).
The pilot study enrolled 35 hospitalized infants and children
Dreizin et al. (36) reported that adult cotton rats were
permissive for RSV infection. Prince and coworkers have used
the cotton rat extensively to study RSV pathogenesis and
immunity (115, 116, 118). While ferrets are susceptible to
pulmonary RSV infection up to the time of adolescence,
cotton rats are susceptible throughout life. Histopathologic
changes in cotton rats include rhinitis of moderate severity,
mild bronchiolitis, and pneumonitis. Convalescent animals
develop protective NT antibodies and cellular immunity that
protects the upper airway and the lung from subsequent
infections. Intramuscular immunization of adult nonimmune
cotton rats with live RSV provides solid immunity for immunized mothers and their offspring. Immune mothers transfer
immunity to their offspring mostly in colostrum and milk.
Infants of immunized mothers respond poorly to subsequent
RSV immunization as long as sufficient maternal immunity
persists. Animals that are convalescent from RSV infections
develop complete resistance to pulmonary reinfection which
lasts at least 18 months, but nasal immunity is diminished by 8
months after infection. Passive immunization with convalescent-phase cotton rat serum given intraperitoneally to infant
animals confers little nasal protection yet provides solid pulmonary protection from RSV infection. The level of serum NT
antibodies required to confer pulmonary protection in the
cotton rat (116) is similar to the NT antibody levels reported by
Glezen et al. (49) to be protective for human infants under 2
months of age.
Some lots of commercial standard human immunoglobulin
prepared for intravenous administration (IVIG) contain substantial levels of NT antibodies to RSV (66). Several human
IVIG lots were examined for prophylactic and therapeutic
anti-RSV activity in inbred cotton rats (114). The prophylactic
and therapeutic effects of four commercial lots of IVIG
(Sandoglobulin; Sandoz, Inc., East Hanover, N.J., NT titers
between 2,702 and 9,344) were compared with a high-titered
human serum (NT titer, 2,800), convalescent-phase cotton rat
serum (NT titer, 1,280), and normal nonimmune cotton rat
serum (NT titer, ,20). In all cases the levels of RSV replication were inversely proportional to the NT titers achieved in
the serum of the passively immunized cotton rats (114). It is
noteworthy that animals treated therapeutically had a depressed primary antibody response to infection but were
resistant to reinfection with RSV (114).
The cotton rat model of RSV infection also provided a
means to investigate potentiation of RSV infections by immunization with formalin-inactivated vaccines (117). Cotton rats
were immunized with three doses of the original lot 100
vaccine or with similarly prepared formalinized vaccines. Convalescent animals were challenged intranasally with RSV. The
26
HEMMING ET AL.
Development of RSVIG
Investigators at the Massachusetts Public Health Biologic
Laboratories and MedImmune, Inc. (Rockville, Md.) collaborated to develop RSVIG for use in the pending formal
immunoprophylaxis efficacy trial (125).
During the development of RSVIG, several techniques for
screening individual plasma units for RSV-specific antibodies
were examined. For the efficient and cost-effective production
of RSVIG from pooled human plasma, it is necessary that the
screening process use minimal amounts of plasma. The screening technique must also be amenable to automation. Intuitively, it was expected that enzyme-linked immunosorbent
assay (ELISA) would be the simplest screening method and
the easiest to automate. Several assays were tested: (i) an
ELISA using whole-virus antigens from lysates of RSV-infected HEp-2 cells (125), (ii) direct ELISAs with purified RSV
F and G glycoproteins as the solid phase (101, 140, 142), (iii)
a competitive ELISA with monoclonal antibodies to the F
glycoprotein (3, 6), (iv) live RSV plaque reduction assays with
and without addition of exogenous complement (118), and (v)
a live RSV microneutralization assay (5). Plasma pools were
prepared from ‘‘high-titered’’ units identified by each of the
methods. Each plasma pool was tested in a series of blinded,
controlled, in vivo experiments of RSV prophylaxis in BALB/c
mice. The subsequent analysis showed that the microneutralization assay best identified the plasma pools that protected
the animals from RSV infection. Use of the assay to select
individual plasma units for inclusion in a pool enhanced the in
vivo NT activity of RSVIG by severalfold compared with
standard IVIG. The enhanced activity was documented in the
cotton rat (124) and in RSV immunoprophylactic studies in
young children (55).
RSVIG Studies in Cotton Rats
Figure 1A and B depicts the relationship between cotton rat
serum RSV NT activity, as determined by complement-enhanced plaque reduction, and the amounts of RSV recovered
from lung or turbinate homogenates of infected animals. The
serum neutralizing antibody (A/Long Potash strain) titer required to reduce RSV concentration in the lung by 99% was
390. To achieve a similar reduction in the nose required an NT
titer of 3,500 (124). Figure 2 shows the serum RSV NT titers
achieved (6 the standard error of the mean) in groups of
cotton rats inoculated intraperitoneally 1 day before RSV
challenge with 0.5 g of randomly selected lots of standard IVIG
(n 5 24 animals) or RSVIG (n 5 47 animals) per kg of body
weight or similarly inoculated with 5.0 g of either the standard
IVIG (n 5 20 animals) or RSVIG (n 5 52 animals) per kg.
Figures 3 and 4 compare the titers (log10 per gram of tissue) of
RSV recovered from the lungs or turbinates of each group of
cotton rats when the animals were euthanized 5 days after
passive immunization and of unimmunized controls 4 days
following RSV challenge. As was observed in previous cotton
rat prophylaxis experiments, RSV NT antibodies protect the
lower airway better than the nose and turbinates. Significant
differences in the protective effect are noted between standard
IVIG and RSVIG (P , 0.01) in both the nose and lung. The
treatment outcomes in these studies correlate directly with the
NT antibody titers in the treatment lot or with the dose of
IVIG (or RSVIG) administered (124).
RSVIG Studies in Children
Groothuis and the RSVIG Study Group (54) demonstrated
that infants and children with BPD or congenital heart disease
and infants born prematurely in the months immediately preceding the RSV infection season tolerated the once-monthly
infusion of IVIG in the range of 500 to 750 mg/kg. Consequently, a prospective three-arm, blinded, randomized, controlled trial of RSVIG was implemented. A placebo arm was
not included in the trial because it was deemed unethical to
infuse a placebo into chronically ill children, such as those with
serious congenital heart disease or severe BPD, who would not
personally benefit from the treatment. A total of 249 infants
and young children were studied. Enrollees had either BPD (n
5 102), congenital heart disease (n 5 87), or prematurity alone
(n 5 60). RSVIG was infused monthly (either 750 mg/kg, high
dose; or 150 mg/kg, low dose); 89 control infants received no
RSVIG. The treatment was well tolerated with mostly mild
adverse reactions in about 3% of the 580 total infusions. One
child had a serious reaction with respiratory failure 24 h later.
This child had preexisting severe BPD and died of progressive
(17 patients treated, 18 given placebo). The IVIG treatments
were well tolerated, and short- and long-term follow-up found
the treatment to be safe. The treated patients had significant
reductions in nasal virus (P , 0.01) and significant improvement in oxygenation 24 h after infusion (P , 0.05). However,
the mean duration of hospitalization was not significantly
reduced (3.94 days for 18 control patients and 3.06 days for 17
treated patients) (71). Further studies of parenteral IVIG
therapy of RSV infections have not been done.
Meissner et al. (92) conducted a prospective randomized,
controlled trial of IVIG (Gammimune N; Cutter Biological,
Miles, Inc., Berkeley, Calif.; NT titer, 950) to evaluate protection of 49 children with congenital heart disease or bronchopulmonary dysplasia (BPD) from RSV infection. Twenty-five
patients received monthly infusions of 500 mg of IVIG per kg
of body weight. Six RSV infections were observed in each
group. Though the differences were not significant, the IVIG
recipients tended to become less ill and were hospitalized for
fewer days. The infusions were well tolerated and caused no
evident morbidity. However, the IVIG lot used had insufficient
NT titers to achieve protective levels (116) in the sera of the
enrolled infants.
Groothuis and colleagues reported that RSV infections were
devastating for children with BPD (53). Studies were designed
to test whether high-risk children (BPD, symptomatic congenital heart disease, or prematurity) could be protected from
RSV infection or have less severe disease if passively immunized with IVIG during the RSV season.
Multiple lots of several U.S.-licensed IVIG preparations
were screened, but lots with NT titers exceeding 1,300 at a 5%
concentration were not found. In a compromise, the tolerability and safety phase of the RSV prophylaxis trial was performed with a standard IVIG lot containing a suboptimal NT
titer. Cotton rat studies had suggested that optimal protection
required trough NT titers to be maintained in the range of 200
to 350 (114). The safety and tolerability portion of the trial was
done with two lots of Gammimune-N. The geometric mean
RSV NT titers at a 5% concentration were, respectively, 1,125
and 1,075 (54). Enrollees received their respective doses (one
group received 500 mg/kg, one group received 600 mg/kg, and
one group received 750 mg/kg) monthly from December
through March of 1988 and 1989. Upon the safe completion of
the pilot trial, the investigators expected to proceed to an
efficacy trial of RSV immunoprophylaxis. Again, multiple lots
of standard IVIG were screened. None had a sufficient NT
titer to achieve adequate 30-day postinfusion antibody levels
(trough titers) following sensibly sized, monthly IVIG infusions.
VOL. 8, 1995
27
FIG. 1. Relationship between serum RSV NT titer (complement-enhanced plaque reduction) at the time of RSV challenge and RSV concentrations (log10 PFU
per gram; A/Long) recovered from lung homogenates (A) or from nasal turbinate homogenates (B). E, nonimmune control animals; 1, treated animals with RSV NT
titers. Reproduced from reference 124 with permission of the publisher.
respiratory failure 3 months later. Additionally, five other
children with congenital heart disease died. Of the six deaths,
three were in the high-dose and three were in the low-dose
group. Three deaths were proximately associated with open
heart surgery, and no death appeared related to the immunoglobulin infusions or to RSV infection. During the 3 years of
the study, a total of 64 RSV infections were observed in the
study population (19 in the high-dose group, 16 in the low-dose
group, and 29 in the control group). Significant differences
between the high-dose group and the control group, respectively, included fewer RSV respiratory tract infections (P 5
0.01), fewer hospitalizations (P 5 0.02), fewer hospital days (P
5 0.02), fewer days in the intensive care unit (P 5 0.05), and
less use of ribavirin in the high-dose group (P 5 0.05) (55). The
study demonstrates that passive immunization of selected
high-risk infants and children with RSVIG during the RSV
season substantially reduces RSV infection rates and the
numbers of such children who require hospitalization for RSV
28
HEMMING ET AL.
bronchiolitis and bronchopneumonia. RSV immunoprophylaxis remains investigational pending licensure review by the
U.S. Food and Drug Administration.
Three additional RSVIG trials are presently under way or
just completed. One is a blinded, placebo-controlled, randomized treatment trial in children, without risk factors, hospitalized with RSV LRI. The second is a blinded, placebo-controlled, randomized treatment trial of high-risk children, such
as those enrolled in the completed prophylaxis trial (55),
who are hospitalized with RSV LRI. The third is a blinded,
controlled prophylaxis trial further examining the safety of
RSVIG prophylaxis in infants and young children with congen-
FIG. 3. Yield (log10 PFU per gram) of RSV (A/Long) from the lungs of
groups of cotton rats treated 1 day before RSV inoculation with 0.5 or 5.0 g of
standard IVIG or RSVIG per kg of body weight. GM, geometric mean; NS, not
significant. Reproduced from reference 124 with permission of the publisher.
ital heart disease. The prevention or treatment of RSV infections with immunoglobulins remains investigational pending
analysis of completed studies and review by the U.S. Food and
Drug Administration.
TOPICAL OR INHALED HUMAN IG
AND RSVIG STUDIES
IVIG Topical Studies in Cotton Rats and Owl Monkeys
Pulmonary RSV infections in cotton rats (117), in owl
monkeys (67), and in children may be treated by the parenteral
FIG. 4. Yield (log10 PFU per gram) of RSV (A/Long) from the nasal
turbinates of groups of cotton rats treated 1 day before RSV inoculation with 0.5
or 5.0 g of human IVIG or RSVIG per kg of body weight. GM, geometric mean;
NS, not significant. Reproduced from reference 124 with permission of the
publisher.
FIG. 2. Circulating RSV (A/Long) NT antibody titers (titer21) in groups of cotton rats 24 h following inoculation with 0.5 g of standard IVIG or RSVIG per kg
of body weight compared with inoculation of 5.0 g of IG or RSVIG per kg. PRN, plaque reduction neutralization; NS, not significant. Reproduced from reference 124
with permission of the publisher.
VOL. 8, 1995
29
FIG. 5. Comparison of the yield (log10 PFU per gram) of RSV (A/Long)
from the lungs of cotton rats treated 3 days after infection with systemic
(intraperitoneal) or topical (intranasal) human IG in various doses. Reprinted
from reference 67 with permission of the publisher.
injection of polyclonal human immune globulin (IG) containing sufficient amounts of NT antibody. Therefore, we wondered whether the topical administration of IG into the airway
administered dropwise or by small-droplet aerosol, and containing known RSV NT antibody levels, might also be effective
in the treatment of RSV LRI.
Cotton rats were infected with RSV. At the height of infection, the rats were anesthetized and then treated with
various doses of IG (Sandoglobulin, lot 2.370.069.0; RSV NT
titer, 2,905) instilled intranasally in a volume of 0.1 ml per
animal or inoculated intraperitoneally. Twenty-four hours after treatment, the animals were euthanized, their lungs and
nasal tissues were homogenized, and RSV titers were determined on the homogenates by plaque assay on HEp-2 cells.
Figure 5 depicts the comparative results of these experiments
(67). The topical treatment, approximately 100 mg of IG per kg
of body weight instilled dropwise intranasally in infected
animals on day 3 of RSV infection, effected more than a
100-fold reduction of RSV in infected animals. Topical therapy
required much less IG than parenteral therapy for a comparable response. This study also demonstrated that the effect did
not come from in vitro neutralization. It was not associated
with increased pulmonary pathology and did not prolong RSV
infection (112, 113). RSV-infected owl monkeys were also
treated by intratracheal instillation of IG at doses substantially
below those necessary for comparable reductions of pulmonary
RSV when treated by the parenteral route (70). In a follow-up
study, it was also demonstrated that IG could be nebulized and
delivered as a small-droplet aerosol for the treatment of RSV
infections in cotton rats (109). The effects observed following
the topical treatment of RSV infections were dose related.
That is, pulmonary RSV titers correlated inversely with the
amount of IG instilled or nebulized and also with the RSV NT
titer of the IG.
RSVIG Topical Studies in Cotton Rats
Once RSVIG was available, a simple correlative study, using
previously reported methods (109, 112), was performed to
compare the therapeutic efficacies of RSVIG and standard IG
(68). Groups of 12 adult cotton rats were infected with RSV.
On day 3 after infection, the groups were treated with IG (NT
titer, 1,100) or RSVIG (NT titer, 5,000) (0.05 ml per nostril) in
either 5, 1, or 0.2% concentrations. The results of these experiments are depicted in Fig. 6 and 7. The intranasal treatment
with IG or with RSVIG induced no reduction in the titers of
RSV from the turbinates of any cotton rats in the treated
groups, a result consistent with previous findings. In striking
contrast, significant reductions in pulmonary viral titers (P ,
0.001) were observed in both IG- and RSVIG-treated rats at
5% concentrations. However, the IG reduction was nearly
30-fold less than that observed with RSVIG. These studies
again confirm the effectiveness of topical IG therapy in the
from the lungs of cotton rats (12 animals per group) treated intranasally 3 days
after infection (Long strain) with 0.1 ml of either 5.0 (■), 1.0 (s), or 0.2% (h)
concentrations of human IG (Sandoglobulin) or RSVIG (lot 6, virally inactivated).
from the nasal turbinates of cotton rats (12 animals per group) treated
intranasally 3 days after RSV infection with 0.1 ml of either 5.0 (■), 1.0 (s), or
0.2% (h) concentrations of human IG (Sandoglobulin) or RSVIG (lot 6, virally
inactivated).
30
HEMMING ET AL.
cotton rat (68). They also demonstrate the effectiveness of
higher NT titers which, if the treatment becomes clinically
relevant in humans, would permit the dramatic reduction in
the amounts of antibody that might be required to effect a
predicted outcome.
RSV AND MONOCLONAL ANTIBODIES
CONCLUSIONS
Nearly 40 years have elapsed since the recovery and characterization of RSV. A large medical and virological literature
attests that RSV infections are frequent causes of mild to
severe respiratory illnesses often requiring hospitalization and
occasionally responsible for death in infancy and early childhood in the United States and throughout the world. Primary
and repeat infections fail in most cases to provide long-lasting
immunity and so humans experience repeat RSV infections
throughout life. Fortunately, most repeat infections in normal
hosts are restricted to the upper respiratory tract. Humoral NT
antibody protects the lung more efficiently than the upper
airway and conjunctiva. This likely accounts for the type of
reinfections with RSV.
In this review, we have discussed clinical and laboratory data
demonstrating that the maintenance of circulating NT antibodies above a critical level makes many high-risk patients significantly less likely to experience serious RSV LRI if infected. It
would be preferable to maintain the requisite antibody levels
by immunization. However, an effective vaccine is not yet
available. In the absence of a vaccine, we have demonstrated
that passive immunization of patients at high risk for a morbid
outcome is a safe and effective alternative once RSVIG is
available. Furthermore, animal studies suggest that there may
be therapeutic indications for the use of hyperimmune RSV
immunoglobulins for the parenteral and perhaps inhalation
therapy of RSV infections in selected patients.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
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Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections.

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