A regimen of six weekly shots of a novel vaccine may be an effective long-term approach for patients with allergic rhinitis, sparing them injections once or twice a week for three to five years, according to results of a pilot study published recently in the New England Journal of Medicine. The treatment, Amb 1-immunostimulatory oligodeoxyribonucleotide conjugate (AIC), combines a ragweed-pollen antigen (Amb a 1) that sets off the allergic reaction with a synthetic bit of DNA (phosphorothiotate oligodeoxyribonucelotide immunostimulatory sequence) that stimulates the immune system.
“This pilot study suggests that the clinical effects of AIC appear to be associated with the mechanism of long-lasting immune modulation…. This approach may also be applicable to other substances that lead to allergic reactions,” according to lead author of the study, Peter S. Creticos, MD, who is Associate Professor of Medicine in the Department of Medicine, Division of Allergy and Clinical Immunology, at the Johns Hopkins University School of Medicine in Baltimore.
The randomized, double-blind, placebo-controlled Phase II trial included 25 adults with documented seasonal (fall) allergies to ragweed, 17 of whom completed the trial. Patients were 23 to 60 years old. All patients received six weekly injections before the onset of the first ragweed season and then were monitored during the next two ragweed seasons. AIC was prepared by the same company (Dynavax) and the same lot of standardized ragweed was used throughout the study. No additional injections were given, but patients were allowed to use medications to relieve eye and nasal symptoms that were difficult to tolerate.
AIC had no effect on the primary endpoint—vascular permeability response as measured by level of albumin, a marker of vascular leakage and inflammation that is reduced by standard allergen immunotherapy. However, AIC achieved impressive improvements in symptoms. During the first ragweed season, the group that received the AIC vaccine had improved peak-season rhinitis scores on the visual analog scale, peak-season daily nasal symptom diary scores, and midseason overall quality of life scores compared with the placebo group. A transient increase in Amb a 1-specific IgG antibody was observed in the AIC-treated group, along with a suppression of the seasonal increase in Amb a 1-specific IgE antibody. A reduction in the number of interleukin-4-positive basophils in patients who received the novel vaccine was correlated with lower rhinitis visual analog scores. In the second ragweed season, the clinical benefits of AIC were seen again, and the seasonal specific IgE antibody response was suppressed again, with no significant change in IgE antibody titer during the ragweed season. The novel vaccine appeared to be safe and well-tolerated. No pattern of vaccine-associated systemic reactions or clinically significant laboratory abnormalities was observed.
In the published study, Dr. Creticos indicated that studies have shown that standard allergen immunotherapy produces a less robust improvement in ragweed seasonal symptom scores compared with AIC, with no lasting benefit unless patients are treated with three or four years of treatment. Standard allergen immunotherapy has a much less convenient schedule than AIC, requiring 14 to 27 injections before the beginning of ragweed season.
AIC appears to be better tolerated than standard allergen immunotherapy. No serious adverse events were associated with AIC, including serious local reactions. However, up to 20% of patients who receive standard allergen immunotherapy report systemic reactions. Standard allergen immunotherapy generally utilizes a slow buildup to minimize the risk of allergic reactions. Dr. Creticos and his co-authors wrote, “AIC may offer a safer route of allergen administration that does not sacrifice efficacy.”
The mechanisms by which AIC exerts its effects require further study, he continued, and larger Phase III studies will establish the role of AIC as a therapeutic intervention in ragweed-induced allergic disease.
“The most exciting thing about this study is that it is the first to demonstrate a long-term benefit from a single, brief course of allergen-specific immunotherapy; the extent of benefit during the second season was similar to that of the first. These are promising results,” said David Khan, MD, Assistant Professor of Internal Medicine in the Division of Allergy and Immunology at University of Texas Southwestern Medical School in Dallas. Dr. Khan said that Dynavax is currently sponsoring a large, 30-center, placebo-controlled study to evaluate AIC in an attempt to replicate these findings.
“The FDA typically requires placebo-controlled studies, but it would also be desirable to compare AIC directly with standard allergen immunotherapy,” Dr. Khan commented.
Dr. Khan mentioned some caveats in interpreting the results of the pilot study. The severity of allergic rhinitis in the study population was unclear, as there were no severity criteria required for participation. “The number of antihistamines and decongestants taken during the study suggest that these patients did not have severe allergies. The median number of days of antihistamine use during the second year of the study was only eight in the placebo patients for the entire ragweed season,” he noted.
Further, the magnitude of exposure to ragweed may have influenced the results. In the study, the peak pollen count during the first ragweed season was 50 to 60 grains of pollen per cubic meter in Baltimore. Dr. Khan said the peak pollen count is often 10 times higher in north Texas. In year 2, the pollen count in Baltimore was almost doubled, which is still much lower than an area such as north Texas. “The fact that the vaccine’s effects persisted in year 2, with a higher pollen count, is more encouraging,” he said.
Ragweed allergy is a relatively simple model with one known major allergen. Many patients are allergic to multiple pollens, each of which has several important allergens. Other questions include whether the AIC vaccine technique will be successful in treating more complicated allergens, such as mold, and whether this technique can be applied to polysensitized patients in whom some of the allergens are less well characterized than ragweed, Dr. Khan said.
He also noted that the safety of AIC is a definite plus. “The dose of ragweed allergen used in the study would be considered a high dose for conventional immunotherapy and yielded not systemic reactions. Improvement with conventional allergen immunotherapy, is dose-dependent, but with a higher dose there are more side effects. This may not be the case with AIC, and perhaps even higher, more effective doses could be administered,” he explained.
Proof of Concept
According to William K. Dolen, MD, President of the American College of Asthma, Allergy and Immunology and Professor of Pediatrics and Medicine at the Medical College of Georgia in Augusta, Ga., the most important take-home message is that the pilot study represents proof of concept. “Scientifically, this is very exciting. The authors studied a specially designed vaccine that interacts with specific and nonspecific parts of the immune system. It is impressive that they were able to show an effect in such a small study,” Dr. Dolen said. He added that more data are needed to interpret the study results more closely. For example, there were no data on whether study participants had symptoms other times of the year in addition to the fall or whether they had other allergies.
Dr. Dolen doubted that the AIC vaccine would be available for general use any time soon because there are so many hurdles to cross. For one thing, the average patient on allergy shots is given multiple injections containing as many as 20 different pollens. “This is a single study of one component of one pollen from one plant. To be clinically useful, vaccines would have to be developed to attack multiple pollens, as well as dust mites, animal danders, and molds. It will take a long time to develop those vaccines,” he said. Additionally, the FDA approval process is lengthy and takes years.
©2007 The Triological Society