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DURHAM, N.C. – Male and female mice have significantly different immune responses to different types of HIV vaccines, Duke University Medical Center researchers report. The results mean the most potent HIV vaccines may be gender-specific, necessitating separate delivery techniques and even separate vaccines for men and women, the researchers said.

The Duke team found gender differences were most striking when immunizing mice against HIV with a nasal spray. Nasal spray vaccines trigger an immune response in the mucous membranes, where most HIV infections start. The researchers found that while female mice responded well to the nasal HIV vaccine, male mice developed little, if any, immune response.

"Understanding that different immunization methods cause different immune responses is an important step in developing an HIV vaccine", said Herman Staats, Ph.D., assistant professor of pathology at Duke University Medical Center and senior author of the study. "This initial observation is significant, but we need additional studies to determine if the same gender differences are seen after immunization of humans," said Staats, a member of Duke's Human Vaccine Institute.

The results appear in the December 2004 issue of the Journal of Virology. The work was funded by the National Institutes of Health and supported by Duke's Human Vaccine Institute.

Traditional injected vaccines do not induce immune responses in mucous membranes and have had little success in combating HIV, Staats said. An effective HIV vaccine may need to do more than stimulate an immune response in the blood stream, such as triggering immune responses in the vaginal mucous lining and the colon, where the vast majority of HIV infections occur.

The Duke study's goal was to immunize male and female mice to produce killer T cells, a type of immune system cell, in their mucous membranes. The researchers evaluated three different forms of HIV vaccines. The vaccines were:

-- An HIV peptide, a protein fragment that can stimulate an immune response, delivered intranasally.
-- A DNA vaccine expressing genes for HIV proteins, delivered intramuscularly.
-- A pox virus, called recombinant modified vaccinia Ankara (rMVA), modified to express HIV proteins and injected into the skin. The modified virus cannot reproduce in human cells and has been used for research and vaccine delivery since the 1970s.

The mice were immunized using various prime-boost strategies. This approach involves priming the immune system with one form of a vaccine, such as nasally-administered HIV peptide, then boosting immunity with a different form of the vaccine, such as the modified vaccinia virus injected into the skin.

The Duke study found the best strategy for creating killer T cells in the mucosal tissues of female mice was an HIV peptide prime, delivered nasally, followed by an rMVA shot into skin. But nasal priming did not work well in male mice, Staats said. Male mice had the best immune response in their mucous membranes following rMVA prime and boost shots into skin.

"We really didn't expect to see such a significant male-female difference," Staats said. "Nasal priming did not work in male mice. As we design and evaluate new vaccines, we need to be aware that what works best in women may not work best in men, and vice versa. This applies to HIV as well as other vaccines," he said.

Staats said the underlying cause for the gender difference is unknown and merits future study. Stress caused by housing male mice in small groups could affect their immune response to vaccines, Staats said. Estrogen in female mice could also play a factor in boosting immune response in mucosal membranes – other studies have reported a link between estrogen and immune system activity, he said.

Study co-authors include James Peacock of Duke; Sushila Nordone of Duke, Shawn Jackson of Beth Israel Deaconess Medical Center at Harvard Medical School; Hua-Xin Liao of Duke; Norman Letvin of Beth Israel Deaconess Medical Center; Alicia Gomez Yafal of Therion Biologics Corporation in Cambridge, Mass; Linda Gritz of Therion; Gail Mazzara of Therion; and Barton Haynes, director of the Human Vaccine Institute at Duke University Medical Center.