Rafi Ahmed, PhD, Georgia Research Alliance Eminent Scholar and director of the Emory Vaccine Center, was principal investigator of the research study, and Shane Crotty, PhD, formerly at Emory University School of Medicine and currently a faculty member at The La Jolla Institute for Allergy and Immunology, was first author. Other members of the research team included Emory microbiologist John Glidewell, Phil Felgner, and Luis Villarreal of the University of California, Irvine, and Huw Davies of King's College London.
Although scientists have known that acute viral infections and vaccines produce two types of long-term immune memory that provide protection against disease, they are still learning the details of these immune mechanisms.
Using a new blood test they developed to assess human antigen-specific immunity, the Emory scientists measured memory B cell responses in individuals recently vaccinated with smallpox vaccine (DryVax), in unvaccinated individuals, and in individuals vaccinated between three months and 60 years earlier. The recently vaccinated group showed a significant virus-specific memory B cell response to vaccinia, while the unvaccinated individuals were negative for vaccinia virus-specific memory B cells. Vaccinia virus-specific B cells were detected in most of the previously vaccinated individuals in the study, including those vaccinated up to 60 years after vaccination.
The scientists found that virus-specific memory B cells initially declined after smallpox immunization, but then reached a plateau approximately ten times lower than their peak, where they remained stable for more than 50 years. Although there were significantly fewer memory B cells in the most recently vaccinated group compared to those vaccinated decades earlier, there was no significant change in B cell memory between 20 and 60 years after vaccination. In addition, individuals vaccinated against smallpox maintained anti-smallpox antibodies in their blood for at least 60 years after vaccination, with no indication of decline between 1 and 60 years.
In humoral immunity, the body's first line of defense against infection is antibodies produced by B cells, which are the primary measure of immunity for most vaccines. Memory B cells are responsible for stimulating a rapid antibody response after re-exposure to infection. In cellular immunity, activated T cells kill specific virus-infected cells and also produce cytokines -- proteins that prevent the growth of viruses and make cells resistant to viral infection. Previous studies in mice by Dr. Ahmed have shown that B cell memory can persist even without re-exposure to viral antigens, but this had not yet been demonstrated in humans.
In order to test the functionality of the memory B cells, the scientists revaccinated a group of test subjects who had been vaccinated between 22 and 48 years earlier, and detected 20-fold increases in vaccinia-virus antibodies after the second vaccination. They also tested antibody response to a specific viral protein. In previously immunized individuals they detected an antibody response prior to booster immunization as well as a strong response four weeks after booster immunization. In newly vaccinated individuals, however, the antibody response to the specific viral protein was virtually undetectable.
"The fact that there was an antibody response to this viral protein in individuals vaccinated years earlier, but no response in recently vaccinated individuals, demonstrates the potency and value of maintaining a pool of memory B cells for decades after vaccination," notes Dr. Crotty. The researchers also measured vaccinia-virus-specific T cells, and found that although the level of T cells declined gradually over time, the cells still were present even decades after immunization in most study subjects.
"Immune memory to smallpox vaccination is an excellent benchmark to help us understand the mechanisms of good vaccines and also to understand the longevity and stability of immune memory in the absence of revaccination or disease," said Dr. Ahmed. "Our findings may be useful as decisions are made about re-instituting a smallpox vaccination program. And because smallpox has an incubation period of from 12 to 14 days, this provides a window of opportunity for memory B and T cells to expand and attack the infection before the onset of clinical disease."
Dr. Crotty said, "Our findings may help assist health authorities in their decision-making process about updates or changes to the smallpox vaccination program. Our work has not shown that these people would be protected, because that cannot be directly tested, and this is an important point. But, our study does show that people maintain immune memory against smallpox for many decades, and hopefully those levels of immune memory would provide at least some amount of protection against smallpox."