Vaccine-induced antibodies that facilitate smoking cessation by blocking nicotine penetration into the brain also markedly reduce the drug's passage across the ex vivo human placenta, a NIDA-funded study has demonstrated. The finding suggests that maternal immunization during pregnancy may be safe and may to some extent protect the fetus from exposure to nicotine.
The adverse effects of maternal smoking during pregnancy include increased rates of miscarriage, premature delivery, low birth weight, neonatal mortality, and sudden infant death syndrome (SIDS). Increasingly, research has linked prenatal smoking exposure to children's neurobehavioral problems, such as attention deficit-hyperactivity disorder. The role of nicotine in causing this damage is not entirely clear, but animal studies suggest the drug may compromise fetal development directly or through its effects on the placenta. "We desperately need medications that can help women quit smoking during pregnancy, medications that are both effective and do not themselves harm the fetus. This study supports the potential use of immunization," says Dr. Paul Pentel of the University of Minnesota Medical School, one of the investigators.
The Experimental Procedure
NicVAX, a vaccine being developed by Florida-based Nabi Biopharmaceuticals with NIDA support, joins the nicotine molecule to a protein. The resulting molecule provokes the production of antibodies that combine with circulating nicotine to create a complex molecule that is too large to cross the blood-brain barrier. When the amount of nicotine reaching the brain drops far enough, the concept goes, "the smoker will no longer get a rewarding effect and will quit," says Dr. Scott Winston, a Nabi researcher. A recent small-scale clinical study found doserelated improvements in 30-day quit rates among 68 immunized smokers ("Nicotine and Cocaine Vaccines Move Forward (Archives)").
The two antibodies used in the placenta transfer study, nicotine immune globulin (Nic-IgG) and a monoclonal antibody (Nic311) were taken, respectively, from rabbits and mice that produced them in response to immunization with NicVAX. The research team, headed by Dr. Mahmoud Ahmed of the University of Texas Medical Branch, Galveston, tested the antibodies' effects on placental tissue and cross-placental nicotine transfer using a method developed in the mid-1980s: An intact lobule was dissected from placentas taken immediately after delivery and placed in phosphate-buffered saline. The researchers inserted catheters into blood vessels on the maternal and fetal side of the placental lobule and perfused each with tissue culture medium from a separate reservoir, creating distinct maternal and fetal circuits. They monitored placental function and viability for 2 hours, and then added nicotine to the fluid in the maternal reservoir. "We used a concentration (40 ng/mL) that has been reported in the circulation of mothers who smoke," Dr. Ahmed says. Either Nic311 or Nic-IgG along with nicotine was added to the maternal reservoir. Following these infusions, the researchers continued to monitor placental tissue health and tracked nicotine and antibody concentrations in both maternal and fetal circuits for 4 more hours.
"Our primary interest in these studies was vaccine safety: Would it be safe to vaccinate women who may become pregnant, or during pregnancy? Antibodies might protect the fetus, but we also worried that they might escort nicotine across the placenta or sequester it in the fetus, increasing exposure," says Dr. Pentel. "The studies look reassuring."
When nicotine alone was added to the maternal circuit, it readily crossed the placenta; its concentration in the fetal circuit increased rapidly over the first 30 minutes. It did not change in the next 210 minutes. The addition of either antibody markedly reduced the rate at which nicotine crossed the placenta. With Nic311, nicotine reached a concentration of 1.8 ± 0.8 ng/mL in the fetal circuit in the first 5 minutes—about one-fourth of the transfer in the absence of the antibody. There was no significant increase in fetal circuit nicotine after the first 30 minutes. Nic-IgG had an even more pronounced effect: The concentration of nicotine in the fetal circuit was about one-half what it had been with Nic311 after the first 5 minutes (1.0 ± 0.04 ng/mL); it, too, rose little after that. Both antibodies also reduced the amount of nicotine retained in placental tissue.
"There was no effect of nicotine or either antibody on placental function or viability," Dr. Ahmed says. No appreciable amount (less than 1 percent) of either antibody appeared in the fetal circuits at any point in the experiment, suggesting that placental transfer was negligible.
Whether vaccination would protect the fetus from nicotine if a mother continued smoking is not yet clear. "I'm not sure that the effect would be large enough," Dr. Pentel says. Previous animal studies in which he was involved found that while antibodies sharply slow the rate at which a single dose of nicotine reaches the brain, they do not stop the process altogether. "When nicotine is administered chronically in a way that approximates daily smoking, its long-term accumulation in the fetal brain looks the same in vaccinated and unvaccinated animals." Vaccination of pregnant rats reduced nicotine transfer to the fetal circulation and brain for 25 minutes after a single dose, but did not change accumulation in the fetal brain when nicotine was administered chronically. In another study, maternal vaccination did not prevent nicotine-induced upregulation of nicotinic cholinergic receptors or changes in gene expression (c-fos) in the fetal rat brain, Dr. Pentel observes. The ex vivo system used in the current study is not intended to model the effects of continual daily smoking, he says, but rather provides insight into the shorter term effects of antibodies on nicotine transfer across the placenta, as well as placental viability.
Dr. Amrat Patel, of NIDA's Chemistry and Pharmaceutics Branch, says the current study represents an important advance beyond animal research in suggesting that nicotine-specific antibodies can reduce placental transfer of nicotine in humans as well, but more work is needed to know whether the effect will be sufficient to prevent neurotoxicity. "We need to determine how much nicotine is necessary to cause fetal damage, and how to make sure nicotine does not approach that level." Antibodies with higher affinity for nicotine may make a difference, he says; as vaccine research continues, "we'll probably progress to develop antibodies that are even better able to sponge up nicotine."
Nekhayeva, I.A., et al. Effects of nicotine-specific antibodies, Nic311 and Nic-IgG, on the transfer of nicotine across the human placenta. Biochemical Pharmacology 70(11):1664-1672, 2005. [Abstract]