Effectiveness of RSVIG prophylaxis and therapy of respiratory syncytial virus in an immunosuppressed animal model

Abstract

Summary:Respiratory syncytial virus (RSV) has emerged as a leading cause of pneumonia, with high mortality, in bone marrow transplant (BMT) recipients, as well as in other profoundly immunocompromised patients, such as myelosuppressed adults with leukemia. We tested the efficacy of immunoglobulin with high anti-RSV neutralizing antibody levels (RSVIG) for prophylaxis and therapy of RSV infection in cotton rats undergoing prolonged immunosuppression with cyclophosphamide. These animals experience persistent infection, a model which is similar to the disease seen in post-BMT humans. Both prophylaxis and therapy reduced pulmonary viral replication over 500-fold to nearly undetectable levels. In animals receiving continual immunosuppression, the use of multiple therapeutic doses of RSVIG was able to prevent rebound viral replication, though virus was not completely eliminated. Keywords: RSV; BMT; immunotherapy; RSVIG; cyclophosphamide; cotton rat Advances in bone marrow transplantation (BMT) have led to a large increase in the number of procedures done, partially due to increasingly aggressive attempts to cure patients of several types of malignancy as well as a variety of other systemic diseases. However, gains due to improvements in BMT are still offset by high rates of morbidity and mortality due to infectious diseases in the immediate post-transplant period. A variety of methods have been effective in reducing rates of some early opportunistic infections, such as cytomegalovirus and Pneumocystis carinii. 1 In contrast, respiratory syncytial virus (RSV), a ubiquitous respiratory virus considered by many to be a significant pathogen only during infancy, has emerged as a major cause of morbidity and mortality in BMT recipients of all ages. 2 Attempts to treat this infection with the antiviral agent ribavirin have been largely unsuccessful, and BMT patients who develop RSV pneumonia have extremely high rates of mortality. [3][4][5][6] IVIG with high anti-RSV activity (RSVIG) is effective Materials and methods AnimalsWeanling inbred cotton rats (Sigmodon hispidus) were obtained from Virion Systems Inc. Animals were housed in large polycarbonate cages in small groups, and were provided water and rat chow ad libitum. ImmunosuppressionAnimals were treated with intraperitoneal (i.p.) injections of cyclophosphamide (CY) at a dose of 50 mg/kg three times weekly for at least 21 days prior to viral challenge. Immunosuppressive therapy was continued until the end of each experiment. To monitor the level of immunosuppression during these experiments, selected suppressed and control animals were bled for complete blood count (CBC) and white blood cell differential counts at the time of viral challenge. Nasal and pulmonary virus titers were determined at several intervals post viral challenge. VirusThe long strain of RSV (Group A), obtained from the American Type Culture Collection, was used as the challenge virus. A single pool propagated in HEp-2 cells containing 1 × 10 6 plaque forming units (p.f.u.) per ml was used for all ...

Palivizumab is highly effective in suppressing respiratory syncytial virus in an immunosuppressed animal model

“…Throughout this experimental series, standard doses of palivizumab led to reductions of RSV achieved previously by only large doses of RSVIG, indicating that palivizumab is more efficient. In fact, in our past work with RSVIG, we used a total of 2 g per kg over 15 days to prevent rebound of RSV replication in persistently suppressed animals, 6 while in the current series of experiments we achieved greater suppression with a total dose of only 60 mg per kg of palivizumab. Recent attempts to treat stem cell transplant patients with severe RSV pneumonia have relied on regimens which combine large doses of RSVIG and aerosolized ribavirin.…”

“…Since viral replication continues at a constant high level in pulmonary and nasal tissues for more than 2 weeks in CY-suppressed animals, 6 it is possible that there could be a rebound of viral replication in suppressed animals after single-dose palivizumab therapy. Three groups of 16 CYsuppressed animals received one of the following: 15 mg/kg of palivizumab therapeutically 3 days after infection; four sequential doses of palivizumab (each at 15 mg/kg) on days 3, 7, 11 and 15 post-RSV infection; or no MAB.…”

“…Three groups of 16 CYsuppressed animals received one of the following: 15 mg/kg of palivizumab therapeutically 3 days after infection; four sequential doses of palivizumab (each at 15 mg/kg) on days 3, 7, 11 and 15 post-RSV infection; or no MAB. The multiple-dose regimen was extrapolated from a past experiment with RSVIG, 6 during which rebound occurred in those CY-suppressed animals treated once, but not in those which received multiple IG treatments 4 days apart. Two identical groups of non-suppressed animals received either a single therapeutic dose of palivizumab (15 mg/kg) 72 h post infection, or no therapy.…”

“…Also, high pulmonary and nasal RSV titers (5-6 logs/g tissue) are present for at least 16 days in continually suppressed animals, while no virus is recovered from either nasal or pulmonary tissue on or after day 8 in control animals. 6 …”

“…5 We recently reported a modification of the use of that model where, by prolonged high-dose cytoxan immunosuppression, we replicated the persistent RSV pneumonia seen in stem cell transplant recipients. 6 In that paper, we demonstrated the ability of a human commercial polyclonal high anti-RSV activity IgG preparation (RSVIG or Respigam) to control RSV replication when given either prophylactically or therapeutically. We return to that model to test the use of the next generation of the product, the humanized anti-RSV monoclonal antibody (MAB) palivizumab (Synagis).…”