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The first clinical trials to test whether the 2009 H1N1 influenza vaccine can safely elicit a protective immune response in pregnant women launched yesterday, and a trial to conduct the same test in HIV-infected children and youth will begin next week. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group is conducting the studies, which are sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.
"These studies are important because HIV infection and pregnancy both increase the risk for a poor immune response to the normal 15-microgram dose of seasonal influenza vaccine given to the general population," says NIAID director Anthony S. Fauci, MD. "Moreover, children, young people and pregnant women are at higher risk for more severe illness from the 2009 H1N1 influenza virus than other groups, and HIV-infected individuals in these populations may be particularly vulnerable."
"Because of the increased vulnerability of these populations, these trials are testing whether doses of licensed 2009 H1N1 influenza vaccine that are higher than doses being tested in other groups can safely elicit protective immune responses in HIV-infected children, youth and pregnant women," adds Lynne Mofenson, MD, chief of the Pediatric, Adolescent and Maternal AIDS Branch in NICHD.
One trial will enroll 130 HIV-infected pregnant women ages 18 to 39 years who are in their second or third trimester (14 to 34 weeks) of pregnancy. The other trial will enroll 140 children and youth aged 4 to 24 years who were infected with HIV at birth.
Thirty-five sites and eight sub-sites across the United States and Puerto Rico are eligible to conduct the trials. Each volunteer will receive two 30-microgram doses of 2009 H1N1 influenza vaccine 21 days apart. (In contrast, the NIAID studies of 2009 H1N1 influenza vaccine in HIV-uninfected children, youth and pregnant women are testing doses of 15 and 30 micrograms.)
Safety data will be collected and monitored closely by the study investigators and an independent safety monitoring committee. The strength and longevity of the immune response elicited by the vaccine will be gauged in several ways.
The study team will take blood samples from the pregnant women after each dose and three and six months after delivery to measure the concentration of antibodies the women produce against 2009 H1N1 influenza virus and how strong that antibody response remains over time. After the women give birth, study staff will sample umbilical cord blood to measure the concentration of maternal antibodies against the H1N1 virus that were transferred to the infants through the placenta. The study team also will collect small blood samples from the infants at 3 and 6 months of age to measure their level of maternally derived antibody protection from the virus over time. The infants will not receive vaccine.
Similarly, in children and young people, the strength and longevity of the immune response will be gauged by testing blood samples taken 21 days after the first dose, 10 days after the second dose, and six months after entering the study.
The vaccine, manufactured by Novartis Vaccines and Diagnostics, contains inactivated 2009 H1N1 influenza virus, so it is impossible to become infected with the virus by receiving the vaccine. The vaccine does not contain adjuvant, a substance added to some vaccines to improve the body's response to vaccine.
Research on seasonal influenza vaccine and vaccines for other diseases in HIV-infected and other populations suggest that higher doses of vaccine tend to elicit stronger immune responses. These stronger responses, in turn, increase the concentration of protective antibodies in the bloodstream, which likely is beneficial to both the vaccinated individual and, if pregnant, to her fetus. This is the rationale for testing whether higher doses of licensed 2009 H1N1 influenza vaccine elicit a protective immune response in HIV-infected individuals and whether that protection is transferred to the fetuses of vaccinated pregnant women.
The National Institutes of Health also is preparing to launch the first government-sponsored clinical trial to determine what dose of the 2009 H1N1 influenza vaccine is needed to induce a protective immune response in people with asthma, especially those with severe disease. The study is cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung, and Blood Institute (NHLBI), both part of NIH.
"People with severe asthma often take high doses of glucocorticoids that can suppress their immune system, placing them at greater risk for infection and possibly serious disease caused by 2009 H1N1 influenza virus," says Fauci. "We need to determine the optimal dose of 2009 H1N1 influenza vaccine that can be safely administered to this at-risk population and whether one or two doses are needed to produce an immune response that is predictive of protection."
The study plan has been submitted to the Food and Drug Administration for review. With FDA allowing it to proceed, the clinical trial will be conducted at seven sites across the United States that participate in NHLBI's Severe Asthma Research Program.
This program already has a well-characterized group of participants with mild, moderate or severe asthma who may be eligible for this new study. These groups are largely distinguished by the amount and frequency of glucocorticoids needed to control asthma symptoms. People with mild disease may not need glucocorticoids, or may require low doses of inhaled glucocorticoids; those with moderate asthma need low to moderate doses of inhaled glucocorticoids; and those with severe asthma need high doses of inhaled glucocorticoids and frequently use oral glucocorticoids as well.
Individuals who already have been infected with 2009 H1N1 influenza or have received a 2009 H1N1 influenza vaccination will not be eligible for the study.
"The results of this study will have immediate implications for individuals with severe asthma as well as those who have milder asthma," says NHLBI director Elizabeth G. Nabel, MD.
Early results from other clinical trials of 2009 H1N1 influenza vaccines in healthy adults have shown that a single 15-microgram dose of 2009 H1N1 influenza vaccine without adjuvant is well tolerated and induces a strong immune response in most participants. The same vaccine also generates an immune response that is expected to be protective in healthy children ages 10 to 17 years. Ongoing trials are comparing the immune response to one and two doses of 15- or 30-micrograms of vaccine given three weeks apart in various populations.
The Centers for Disease Control and Prevention has recommended that certain at-risk populations receive the new H1N1 vaccine as a priority before the general population. These target populations include pregnant women, health care providers and individuals with underlying chronic medical conditions, including asthma.
People who have severe asthma may be particularly at risk for infection with the 2009 H1N1 influenza virus. A report published in 2004 suggested that some people who took high doses of glucocorticoids to treat their asthma may receive less protection from influenza vaccines against some strains of influenza. Early in the 2009 H1N1 flu outbreak a CDC review of hospital records found that people with asthma have a four-fold increased risk of being hospitalized with infection compared to the general population.
The study will enroll approximately 350 people with mild, moderate and severe asthma. Participants will be organized into two groups: those with mild or moderate asthma and those with severe asthma. Half of the participants in each group will receive a 15-microgram dose of vaccine, and the other half a 30-microgram dose. Three weeks later, each participant will receive a second dose of the same amount. The strength of the immune response induced by the vaccine will be determined in blood samples by measuring the level of antibodies against 2009 H1N1 flu virus.
Safety data will be collected and examined throughout the course of the study by trial investigators and by an independent safety monitoring committee. Participants will be monitored for any side effects they may experience because of the vaccine, as well as asthma attacks that occur during the study period.
The vaccine to be used in the trial, manufactured by Novartis, contains inactivated 2009 H1N1 influenza virus and therefore cannot cause anyone to become infected with the virus.
The trial will be conducted at the following locations:
•Cleveland Clinic, Ohio
•Emory University, Atlanta
•University of Pittsburgh Asthma Institute
•University of Virginia, Charlottesville
•University of Wisconsin, Madison
•Wake Forest University, Winston-Salem, N.C.
•Washington University School of Medicine, St. Louis