The biologics industry has experienced tremendous growth, owing much to the development of vaccines that have helped counter infectious disease crises threatening public health on a global scale. However, vaccine development remains a costly venture, with antigen expression absorbing the bulk of manufacturers’ monetary resources, leaving consumers to absorb the cost of expensive vaccines downstream. Unfortunately, the high price point often limits the accessibility of these potentially life-saving products to low-income populations. The commonly used aluminum-based adjuvants, or substances that help encourage an immune response when they encounter antigens, demonstrate moderate efficacy and unfavorable side effect profiles.

Now, a promising new study has demonstrated that introducing different adjuvants can enhance the humoral immune response while reducing the potential for side effects and controlling manufacturing costs. The results of these findings were published in a recent issue of Materials Today.

“Sometimes changing a small thing in the material might have a large effect on the biology side,” says Sabine Szunerits, professor of chemistry at the Université de Lille in France and corresponding author of the study. “What we change here is the morphology; the chemicals stay the same, but this product has a very different, better, and less toxic effect than the others.” 

Certain cells in the immune system constantly circulate throughout the body, actively monitoring for foreign cells. Any cells identified as foreign, or non-native, elicit a response from the immune system upon discovery. However, foreign cells must be large enough for immune cells to “see” in order to generate an immune response.

Vaccines produce immune responses by exposing the body to a small amount of foreign proteins, or antigens, to which the immune system forms antibodies upon discovery. To help the immune system identify these cells and increase the immunogenicity, or immune response, scientists attach “helper” particles to the antigens called adjuvants. Adjuvants offer the additional benefits of reducing the amount of antigen needed to induce a response from the immune system. Aluminum hydroxide and aluminum oxyhydroxide, commonly known as “alum,” are currently the most commonly used adjuvants in human vaccines.

Previous research demonstrated the enhanced immunogenic response of neutrophils (special white blood cells that are the first-responders in fighting infections) toward antigens when nanoparticles of varying sizes were injected simultaneously. The neutrophils responded by forming aggregates called neutrophil extracellular traps (NETs) that surround and sequester the antigens. The researchers in this new study elaborated on this concept. They altered the shape and size of adjuvants by synthesizing Al₂O₃ nanowires using a previously established protocol in which they dealloyed bulk aluminum-lithium alloys in the presence of alcohol at 60°C for 24 hours. They subsequently heated the microstructures to 800°C for one hour. The result was the formation of aluminum oxide-based nanowires of uniform diameter averaging 20 nm.

The abrasive surface and sharp edges of the nanowires, which the research team characterized by electron microscopy, promoted NET formation when injected into mice. The research team analyzed the humoral (B cell response and antibody production) and cellular responses (production of T cells and hypersensitivity reactions) in albino mice bred in the laboratory called Balb/c mice injected with alum, g-Al₂O₃, Al₂O₃ microparticles, or ovalbumin (OVA, from a chicken egg) alone when used as adjuvants. Fourteen days later, the researchers observed moderate increases in anti-OVA IgG antibodies from all adjuvants with the g-alum nanowire + OVA adjuvant displaying the most immunogenic response. Thirty-five days after immunization, a significantly higher (up to 4 times) number of antibodies had formed in the serum of mice injected with g-alum nanowire + OVA than the other groups. The nanowires produced strong humoral immune while preserving the microvasculature.

“The authors showed that ultra-long and thin Al₂O₃ nanowires with a high aspect ratio of ∼1000 can significantly boost the adjuvant efficacy of alum,” says Aliasger Salem, head of the division of pharmaceutics and translational therapeutics and a professor at the College of Pharmacy at the University of Iowa, who was not involved in this study. “If you can take an adjuvant like alum and increase its efficacy by changing the size, shape, aspect ratio, and crystallinity, then you can achieve the same adjuvant effects at lower concentrations of alum.”

Like the study’s authors, Salem believes the finding of this research translates into the potential to reduce local side effects and reduce the cost of each dose resulting from the reduced production costs associated with the nanowires.

Read the abstract in Materials Today.