Effective vaccines for many complex infections, like malaria, remain elusive or ineffective because they require both protection against pathogens and specialized immune cells to clear infected cells.
Though a vaccine for malaria exists, it is only effective in 30 to 50 percent of patients, and malaria is still responsible for nearly 500,000 deaths annually, according to the Centers for Disease Control.
Researchers at the Institute for Molecular Engineering at the University of Chicago have developed a new system for delivering a malaria vaccine that shows promise in being much more effective than the current system. By developing a vaccine that targets specific cells in the immune system, they have seen a much greater immune and antibody response to the vaccine.
“When compared to the current malaria vaccine option, our results are extremely exciting,” said Jeffrey Hubbell, Eugene Bell Professor in Tissue Engineering and corresponding author on the paper. “This work could potentially have applications in vaccinations against complex infections and cancer.”
The results were published Jan. 14 in Nature Materials.
Developing an effective subunit vaccine
Though vaccines are routine in public health, they do not all work the same way. Researchers have developed several strategies for generating immunity in patients. For example, live-attenuated vaccines, which use a weakened form of the disease, provide immunity from diseases like measles, mumps, and rubella.
One of the safest and easiest vaccine platforms is the subunit vaccine. Instead of using a weakened form of a pathogen causing a disease, researchers take proteins derived from the pathogen — called antigens — and formulate them with a compound — called an adjuvant — that induces a pro-inflammatory response. In the body, the antigen introduces the disease to the immune system, while the adjuvant activates pathogen-specific T cells, which help clear infected cells. This type of vaccine is used for whooping cough, HPV, and malaria.
While the field has had success developing subunit vaccines with effective antigens, researchers have found less success with adjuvants, mainly because it is difficult to localize their delivery to the right location within the body. If such molecules aren’t targeted, they can cause inflammation throughout the body, which can be fatal.
Directing the delivery
Hubbell and his colleagues approached this problem with a subunit malaria vaccine as a delivery issue. To deliver the vaccine to its intended target, they developed a vaccine platform made up of a polymeric adjuvant — which contains multiple adjuvant molecules connected like pearls in a necklace — coupled with an antigen. This vaccine platform can easily drain into the secondary lymphoid tissues and deliver the vaccine to specific cells that make up the body’s immune system.
To make sure it found its way to the intended site, they incorporated mannose, a type of sugar, into the polymeric adjuvant. Because viruses and bacteria tend to have a lot of sugar on their surfaces, the dendritic cells in the lymphoid tissues have several sugar receptors that help in the recognition of pathogens.
So once the mannose-laden vaccine is injected into the body, it targets specific immune cells, called dendritic cells, which in turn activate T cells. By specifically targeting dendritic cells, this new technology prevents systemic inflammation while efficiently activating an immune response.
“It’s a targeting material, but it is also inherently therapeutic,” said D. Scott Wilson, a postdoctoral researcher in Hubbell’s lab.
When tested, the vaccine system had a higher antibody response than the malaria vaccine currently on the market. It also provided a cellular response — clearing the infected cells — which the current vaccine does not do.
Researchers have now partnered with Emory University to continue testing the system and hope to develop similar models for cancer and flu vaccines.
Other authors on the paper include Melody Swartz, William B. Ogden Professor; students Michal Raczy and Ruyi Wang; senior scientist Marcin Kwissa; postdoctoral researcher Maria Broggi; Sachiko Hirosue, Laura Jeanbart, Giacomo Diaceri, Xavier Quaglia-Thermes of the École Polytechnique Fédérale de Lausanne; and Leonardo Bonilla-Ramirez, Jean-Francois Franetich, and Dominique Mazier of the Centre d'Immunologie et des Maladies Infectieuses.
Citation: “Antigens reversibly conjugated to a polymeric glyco-adjuvant induce protective humoral and cellular immunity.” Wilson et al, Nature Materials, Jan. 14, 2019. doi: 10.1038/s41563-018-0256-5
Funding: Whitaker Foundation, School of Life Sciences EPFL, and the University of Chicago.