Super Vaccine of the Future: The More Carbs the Better

Fikri Avci and Dennis Kasper

Every year, we vaccinate people to protect against disease. However, even with our best intentions, protection from pathogens is not guaranteed. Sometimes a vaccine that may protect one population may fail to be effective in another. But BWH researchers are on the path to creating a new generation of more potent vaccines.

Fikri Avci, PhD, instructor in the Department of Medicine at BWH and Harvard Medical School, and Dennis L. Kasper, MD, director of the Channing Laboratory at BWH, in collaboration with two Rockefeller University scientists, have developed a glycoconjugate vaccine prototype 50 to 100 times more effective than the traditional glycoconjugate vaccine. Comprised of carbohydrate and protein molecules, a glycoconjugate vaccine is the standard design for many vaccines used to protect against common diseases like pneumonia and meningitis. Their work is published in the December 2011 issue of Nature Medicine.

Researchers designed the vaccine prototype after discovering that immune cells, called T-cells, can recognize a vaccine’s carbohydrates, and from that recognition elicit an immune response. This discovery challenges popular assumptions that immune cells only recognize the protein portion of glycoconjugate vaccines.

“The immunologists knew it was only the peptides (proteins) that were recognized by the T-cells,” said Fikri. “So then they extrapolated this idea in the context of glycoconjugate vaccines.”

Proof in the Sugar

Proof that T-cells recognize carbohydrates came when researchers immunized mice with different types of glycoconjugate vaccines against the bacteria, group B Streptococcus. One group was immunized with vaccines containing different proteins. Another group was immunized with vaccines with the same proteins. For both groups, the carbohydrate chain in the vaccines was the same.

Researchers saw that mice given the vaccines with different proteins had just as good an immune response as those given vaccines with the same proteins—the variability in proteins did not change immune response. This told researchers that T-cells must have been recognizing other molecules to generate a consistent immune response. They had come upon a type of T-cell that recognized carbohydrates.

“One thing that is tremendously novel here is that we were able to find T-cells within a mouse after immunization with a glycoconjugate [vaccine] that just recognized carbohydrates,” said Kasper. “So these may be the first true carbohydrate-specific T-cells found.”

In addition, the research community also assumed that after breaking down a vaccine, the immune system disregarded the carbohydrates and only processed the proteins to generate an immune response. Avci and colleagues showed that this was not the case. Rather, when B-cells (another type of immune cell) broke down the vaccine, the carbohydrates were paired with the peptides (i. e., degradation product of proteins) on the B-cell surface where they would be recognized by T-cells to trigger the cells to make antibodies.

The Element of Design

Knowing that carbohydrates were being presented and recognized to elicit an immune response, the next step was to design a vaccine that would yield as many of these carbohydrate-peptide particles during the breakdown process. The more of these particles, the greater the immune response.

Traditional glycoconjugate vaccines usually yield only one to two carbohydrate-peptide particles after they are broken down by B-cells. To better understand why, consider proteins in traditional vaccines as bulky blob shapes, and carbohydrates as long chains. Laying the chain along a row of blob-shaped proteins, there are only a few points where the carbohydrate chain can come in contact with the protein because of the protein’s bulky shape. When B-cells break apart the vaccine, what results are only a few carbohydrate-peptide particles. The rest of the vaccine is wasted.

Imagine the same carbohydrate chain lined along tinier proteins with a more uniform shape, appearing like a string of holiday lights. With the tinier, more uniform proteins the carbohydrates are able to come in contact at more points. So when the vaccine is processed, the results are more carbohydrate-peptide particles. This is the vaccine prototype Avci and his colleagues developed, and what bested the traditional vaccine in boosting immune response. “We think this technology can be used to improve on the design of any vaccine,” said Kasper. “Even when glycoconjugate vaccines are used, they are not effective in all at-risk populations. For example, pneumococcal conjugate vaccines are good in children, but are not effective in protecting the elderly.”

Moving Forward

Avci acknowledges that there is still a lot to learn about how the immune system responds to glycoconjugate vaccines.

“We know carbohydrates are processed and presented to T-cells, and T-cells recognize them,” said Avci. “But the molecular interactions and through which portion of the T-cell receptor binds to the carbohydrate—all of these will need structural biochemistry experiments.” For now, the findings surrounding the immune system’s response to carbohydrates provides hope for more effective vaccines of the future.

“Carbohydrates are among the most abundant and structurally diverse molecules in nature,” said Avci. “They are extremely important in many biological functions. A better understanding of carbohydrate interaction is crucial. We are hoping that our findings will provide a framework for production of new-generation therapeutics and preventive medicines not only against bacterial infections, but also for cancer and viral diseases.”

Molecules in traditional glycoconjugate vaccines appear as bulky, blob shapes.

BWH researchers used a streamlined design resembling a string of holiday lights to accommodate as many carbohydrate and protein molecules as possible.