Study of vaccine effect on mitochondrial disorder seeks participants

Cornelia Dekker

The Stanford University School of Medicine is recruiting participants for a clinical trial to determine whether people whose energy metabolism is compromised by a mitochondrial disorder respond differently from normal subjects to the standard seasonal influenza vaccine.

The pilot study will involve 15 people ages 13-60 who either have a mitochondrial disorder known as MELAS syndrome or are carriers for the genetic syndrome — typically family members of diagnosed patients — and 15 healthy subjects ages 18-65 to serve as controls. Family members of patients diagnosed with this disorder are particularly encouraged to enroll in the trial, said Gregory Enns, MD, one of the principal investigators for the study, which is now under way.

“We’re using very advanced assays to take a look at metabolites and measures of immune response. We’re looking for any significant differences between MELAS patients or carriers and healthy subjects, both before and after immunization,” said Cornelia Dekker, MD, the study’s other principal investigator. Dekker, professor of pediatric infectious diseases and medical director of the Stanford-Lucile Packard Children’s Hospital Vaccine Program, is responsible for initiating and carrying out clinical trials of vaccines at Stanford.

Scattered clinical observations have raised concerns that vaccinating MELAS or other mitochondrial-disease patients might overstress their metabolism, possibly contributing to the manifestation or worsening of symptoms in previously asymptomatic children who are genetically predisposed to such disorders. But to date, no controlled study has shown any causal relationship between vaccination and mitochondrial-disorder-associated symptoms. The Stanford study is the first to test for such an association. Meanwhile, the U.S. Centers for Disease Control and Prevention recommend that MELAS and other mitochondrial-disease patients be vaccinated annually for influenza, and the great majority of physicians agree that contracting influenza is a far greater stress on these patients than any vaccine.

Mitochondria, found in large numbers in every cell in the body, are to cells what engines are to cars. It is in the mitochondria that calorie-rich substances from food are combined with oxygen to make the energy that powers activity within each cell. Thus, they are the power source for all activity in the cell.

“But as with cars, even the best-tuned engine gives off some ugly exhaust when it is forced to work too hard,” said Enns, an associate professor of pediatrics whose research focuses on mitochondrial disease. “And just as a misfiring engine can make a car’s exhaust pipe release huge plumes of noxious smoke into the air, mitochondria that aren’t working right can release ‘biochemical smoke’ — chemical toxins such as free radicals and excessive lactic acid — into the cell, and ultimately into the blood and urine. We’re looking for these biochemical markers of mitochondrial malfunction.”

MELAS syndrome, probably the most common of a group of relatively rare disorders caused by mutations in mitochondrial genes, affects perhaps one in 5,000 people. MELAS syndrome varies greatly in both its severity and its particular manifestations from one individual to the next. Symptoms can range from none at all to migraine headaches or tingling in the extremities to cognitive or motor disorders, learning or language disabilities, hearing loss or diabetes. It can remain undetected for decades or a lifetime. In some cases, the disorder has been first diagnosed in people who are already in their 60s.

The investigators said their findings in this trial may someday prove useful not only to MELAS patients or those with similar genetic mitochondrial defects, but also perhaps to the rest of us as well. All of us accumulate genetic damage to our mitochondria as we age. Mitochondrial damage, in turn, has been linked to many aging-associated syndromes such as type-2 diabetes, cancer, Parkinson’s, Alzheimer’s and cardiovascular disease.

“Studying people with rare genetic disorders helps us to understand genetics of unaffected people,” said Enns. “These patients are models for all of us.”

All trial participants will receive a single shot of the standard influenza vaccine, licensed for this season by the U.S. Food and Drug Administration. Blood and urine samples from participants will be transferred to numerous researchers, who will analyze hundreds of different substances and cell types from these samples in a coordinated effort to find factors that can help predict a given person’s immune profile and immune response to influenza vaccination.

Prospective participants are encouraged to visit the Stanford-LPCH Vaccine Program Web site, http://vaccines.stanford.edu/clinical_trials.html, to review study information and join the volunteer mail list, or call (650) 498-7284 to learn more about their potential eligibility for the trial. Dekker noted that people considering participation in the trial should be prepared to make four visits to the Stanford campus over a period of about one month. Those selected to participate will be immunized during the first visit, and undergo blood and urine draws at all of them. The second visit will take place six hours after the first, followed by third and fourth visits 5-7 days and 26-30 days after the first visit. While most visits will require a half-hour or less of the participant’s time, the first visit is expected to take up to two and one-half hours because of the informed-consent process and immunization. Enrolled subjects will receive parking vouchers for their visits and compensation for their time ($30 per visit).

The trial is being sponsored by a grant from the National Institutes of Health.