Vol 9. Issue 8 / March 9, 2009

Team Deepens Fundamental Understanding of How Vaccines Work

By Anna Sobkowski

Scientists from the Scripps Research Institute have uncovered the workings of specific immune molecules needed to produce effective vaccines and long-term immune memory. These studies lay the foundation for a new generation of vaccines that can be designed to increase the body's adaptive immune response to foreign proteins.

The study appeared in an advance, online issue of the journal Nature Immunology on March 1, 2009.

In the new study, Professor Michael McHeyzer-Williams, postdoctoral fellow Nicolas Fazilleau, and other Scripps Research colleagues uncovered fundamental rules that govern the quality and quantity of a special type of cell—a major sub-class of helper T cells called follicular helper T cells, or TFH cells—needed to regulate strong antibody responses and long-term immune protection.

"When one measures the antibody class, titer [concentration], and affinity after a vaccination or a vaccine booster, one is broadly measuring the function and effectiveness of this TFH compartment," McHeyzer-Williams says. "Our work reveals some of the basic rules about how these special types of helper T cells are produced upon vaccination."

Using the strategies developed in the current study, that team can now design vaccine adjuvants (additives) that enhance TFH cell development and promote stronger immunity.

The Need for Better Vaccines

While most vaccines in use today depend on the body's immune system to mount a strong antibody response, how to achieve that strong response has not been clear. Because the mechanism of vaccination is poorly understood, making effective vaccines is often a hit or miss endeavor and there are many diseases for which no good vaccines exist despite tremendous efforts to develop them.

Scientists do know that helper T cells are the central regulators of the adaptive immune system, which consists of highly specialized systemic cells and processes that fight off pathogens (disease-producing agents, such as viruses and bacteria). Once activated by the recognition of an antigen (a substance that stimulates the immune system), helper T cells produce chemicals to regulate the production of antibody (a defense protein that binds to foreign molecules) by B cells that can clear infection directly.

Importantly, antigen-specific helper T cells also control the development of high affinity immune memory by B cells that can protect the host for a lifetime. Specific immune memory induced by vaccination enables the immune system to recognize specific pathogens and to mount very strong protective immune responses even upon the first encounter with an otherwise disease-inducing pathogen. 

The current study shows what mechanisms control the number of helper T cells that become TFH cells needed to promote high affinity strong antibody responses. More of these TFH cells would likely promote a larger and stronger memory B cell compartment that provides long-term immune protection.

Using mouse models of protein vaccination, the McHeyzer-Williams group has been able to select adjuvants that drive the greatest TFH cell response. They have shown that the helper T cells with the strongest binding receptor for the foreign protein antigen preferentially become the specialized TFH cells. It is these TFH cells that regulate B cells, antibody class, and affinity, all critical features of protective immunity.

"It looks as if the strength of that initial contact is driving cell fate," McHeyzer-Williams says. "If the helper T cells have a strong receptor for the antigen the first time they encounter it, they are much more likely to become TFH cells. More TFH cells likely means more B cells, which is the desired result."

Building on Previous Work

Working with mouse models over the course of many years, the McHeyzer-Williams group has been able to develop systems that generate helper T cells with a high affinity for foreign proteins.

The scientists study protein vaccines, which make use of a small portion of a pathogen to trigger a strong antibody response and high affinity B cell memory. In the case of a viral pathogen, for example, just a piece of the protein coat that surrounds the virus's DNA or RNA can be enough to trigger a powerful and protective immune response without ever having been exposed to the virus. Monitoring the emergence of specific helper T cells and antigen-specific memory B cells directly after vaccination allows a new means for selecting the right antigen dose, the right means and route of vaccine delivery, and the right vaccine adjuvant.

An earlier paper from this group identified the memory counterpart of the TFH cells as another central component to effective vaccination and the control of the vaccine boost. Both studies spearheaded by Fazilleau provide a new depth of understanding for how protein vaccines will induce effective long-term immune protection. 

"By working at a mechanistic level, we have gained a better understanding of the molecular and cellular rules that regulate the antibody response," says McHeyzer-Williams. "When we apply these rules to new vaccine formulations, we can make more of the right type of cells. Hence, we believe the general strategy for making vaccines could be enhanced."

In addition to Fazilleau, who will be starting an independent research career in Toulouse, France, Scripps Research Scientific Associate Louise McHeyzer-Williams, provided continual guidance and direction to the research project with Scripps Research Institute Professor Hugh Rosen, a valued contributor. For more information on the paper, entitled "The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding," see http://www.nature.com/ni/journal/vaop/ncurrent/abs/ni.1704.html.

The work was funded by the National Institutes of Allergy and Immunology.


Send comments to: mikaono[at]scripps.edu

"By working at a mechanistic level, we have gained a better understanding of the molecular and cellular rules that regulate the antibody response," says Professor Michael McHeyzer-Williams (top right), shown here with co-authors Research Associate Nicolas Fazilleau and Scientific Associate Louise McHeyzer-Williams (left).