Immunotherapy for Infectious Diseases

252 Onorato and Pollard
However, the strategy of immunoprophylaxis with RSVIG-enhanced immune globulin
has flaws. The high volume of immunoglobulin that must be administered carries
risks, as well as the need for prolonged infusion in a monitored setting. The high cost
of the infusions is also prohibitive. For these reasons, a variety of monoclonal antibodies
to RSV have been developed that can be administered in small volumes by intramuscular
injection. Of these, palivizumab (MedImmune, Gaithersburg, MD) has been
shown to have efficacy in the prevention of RSV-associated disease in at-risk children.
Palivizumab is a humanized immunoglobulin G-1 with affinity for the F protein of
RSV and has good activity against clinical isolates of both type A and type B RSV. In
in vitro neutralization assays, palivizumab is 20 times more potent than RSVIG (8).
A clinical trial conducted over the 1996–1997 RSV season showed efficacy of this
antibody in RSV disease in high-risk pediatric populations. At 139 centers in the
United States, United Kingdom, and Canada, 1502 children with either prematurity or
bronchopulmonary dysplasia were enrolled and randomized to receive five injections
of either palivizumab at 15 mg/kg or placebo. Palivizumab prophylaxis resulted in a
55% reduction in hospitalization attributable to RSV infection. The benefit was greatest
in children with prematurity alone as a risk factor, compared with children who had
bronchopulmonary dysplasia. The incidence of adverse events was similar in the treatment
and placebo groups (9). Not surprisingly, the monoclonal antibody to RSV did
not seem to have the same protective effect with regard to otitis media and respiratory
infections other than RSV that the pooled RSVIG provides, since the latter probably
contains antibodies to multiple pathogens. Current guidelines for pediatric prophylaxis
with palivizumab or RSVIG are in Table 1 (10). Prophylaxis should be administered
from the beginning to the end of RSV season.
EBV-ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS
EBV-associated lymphoproliferations arise as complications of organ and marrow
allografts. Rates of EBV lymphoproliferative disorders approaching 10% are seen in
cardiac and cardiopulmonary transplants, probably owing to the intensity of immunosuppression
(11). EBV-associated lymphomas seen after marrow allograft are usually
diffuse large cell lymphomas of B-cell origin, involving both nodal and extranodal
sites, and are oligoclonal or monoclonal. In further contrast, they are of donor rather
than host origin and develop within the window between initial engraftment (3–60 days
post transplant) and return of T-cell function (6–8 months post transplant). These characteristics
suggest absence of host EBV-specific T-cell response as the factor responsible
for the proliferation of donor EBV-transformed B cells (12). Other evidence for the
importance of intact T-cell response comes from in vitro analyses of immune responses
in patients recovering from infectious mononucleosis, which suggest that HLArestricted,
virus-specific T-cells are capable of killing EBV-transformed B-cells and
that HLA-restricted virus-specific CD8� T-cells are likely to be the dominant contributors
to sustained resistance (13–15).
In light of this, transfer of peripheral blood mononuclear cells (PBMCs) from the
respective EBV-seropostive marrow donors to treat EBV-associated lymphoma in marrow
allograft recipients has been attempted. Small numbers are infused (on the order
of 10 5 –10 6 T-cells/kg) PBMCs or HLA partially matched T cells from in vitro expanded
T-cell lines derived from an EBV-seropositive marrow donor. In the largest series of