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Each year in the U.S., about 790,000 total knee replacements and more than 450,000 hip replacements are performed. Despite the use of sterile techniques among surgical teams and prophylactic antibiotics, 2% to 4% of implanted devices become infected.
Decades of effort and multiple trials have not yet resulted in a vaccine that protects patients against Staphylococcus aureus bacteria, the leading cause of orthopedic device infection.
That could soon change.
Researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences and the Wyss Institute for Biologically Inspired Engineering are developing a vaccine aimed at preventing implant-related infections caused by Staphylococcus aureus.
Their findings, published in Proceedings of the National Academy of Sciences, show encouraging results. Mice that were vaccinated five weeks before being implanted with an orthopedic device showed about a 100-fold reduction in bacterial burden compared to mice receiving conventional soluble vaccines containing the same molecular ingredients.
The work is based on years of research into biomaterials-based immunotherapies.
Instead of relying on soluble vaccine formulations that disperse quickly after injection, the research team engineered a slowly degradable scaffold that functions as a localized immune training ground. The scaffold recruits dendritic cells, which are key coordinators of immune signaling, and presents them with a concentrated and sustained array of S. aureus antigens.
“Conventional vaccines deliver their ingredients in a liquid suspension that is injected under the skin or into the muscle and then rapidly dissipates,” said Alexander Tatara, M.D., Ph.D., Assistant Professor at UT Southwestern Medical Center and first author of the study. “By presenting these components in an injectable biomaterial scaffold, we can create a microenvironment that has a relatively high concentration of vaccine ingredients.”
The vaccine lasts longer as the biomaterial degrades over a few weeks, which is key to improving immune efficacy. Dr. Tatara said the current platform provides sustained dendritic cell engagement and specific T-cell responses and activates immune pathways that previous vaccines missed.
“Based on our data, presenting vaccine components in a biomaterial scaffold improves cell-mediated immunity compared to traditional liquid vaccine injections,” he added. “While there’s still much to learn about orthopedic immunology and staphylococcal infection, we suspect that this boost to cell-mediated immunity, specifically T cells that are ‘master regulators’ of the immune response, provides the benefit we saw in the prevention of orthopedic device infection.”
Widespread Protection
A key differentiator in the current vaccine platform is its antigen strategy. Earlier efforts typically targeted one or a small handful of bacterial proteins.
The research team instead used an engineered mannose-binding lectin (FcMBL) technology to capture a broad collection of pathogen-associated molecular patterns (PAMPs) from disrupted S. aureus bacteria.
“Prior vaccine trials for S. aureus have used a single antigen or a cocktail of several antigens,” Dr. Tatara said. “By using an engineered mannose-binding lectin protein, we’re able to agnostically collect PAMPs, which are hundreds of different components that are typically recognized by the body’s immune system to signal that a pathogen is present. By delivering a collection of PAMPs rather than a few antigens, we present more patterns to ‘teach’ the immune system as it seeks to recognize and inhibit S. aureus.”
This broader antigen presentation may also help solve the strain variability of infection-causing bacteria. Methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains differ genetically, which complicates vaccine design.
In the current work, scaffolds constructed with PAMPs derived from MSSA strains also protected implanted devices against subsequent MRSA infection.
“We were happy to find that mice vaccinated with PAMPs collected from one strain of S. aureus had protection against other strains, including MRSA,” Dr. Tatara said. “This speaks to another advantage of using a broad array of antigens such as PAMPs.”
Dr. Tatara said translating this cross-protection to the clinical diversity of human strains remains an ongoing pursuit.
“This is an important issue and an active area of research in our groups,” he added. “We have done preliminary work across some of the most common strains that are associated with device infection, including USA100, USA200, and USA300, and our results are promising so far.”
Practical Use
The researchers believe the vaccine they’re developing could be integrated seamlessly into standard patient care pathways.
“We envision biomaterial vaccines becoming incorporated into the normal preoperative evaluation for arthroplasty,” Dr. Tatara said. “Just as patients are counseled on smoking cessation and glycemic control prior to surgery, they could receive an injectable biomaterial vaccine to prevent device infection as part of their office visits before their surgical dates.”
The team is also exploring therapeutic applications.
“In addition to helping prevent infection as a form of prophylaxis, we are excited about the possibility of using vaccines as personalized immunotherapy for patients with active infection,” Dr. Tatara said.
For example, if a patient has a periprosthetic joint infection, it may be possible to build a custom vaccine against their specific isolate obtained from arthrocentesis. With the increased cell-mediated immunity boost from biomaterials, this strategy could be used as adjuvant therapy as part of DAIR (Debridement, Antibiotics and Implant Retention), one- or two-stage treatment.
The ability to identify a PAMP “signature” from specific bacterial isolates could also inform next-generation vaccine design, potentially enabling streamlined, highly targeted constructs that retain broad efficacy.
The research team’s next steps include continuing to refine the combination of biomaterials, antigens and adjuvants to maximize the efficacy of the vaccine platform, and to better understand how these factors affect specific aspects of immunity.
Clinical trials are to come, and if the vaccine platform is successful in humans, biomaterial scaffold vaccines could fundamentally change infection prevention in orthopedics.
“One could envision a future in which clinical researchers rapidly identify relevant PAMPs in patient-specific S. aureus strains obtained through simple non-invasive procedures ahead of surgeries to produce effective personalized biomaterial vaccines that protect implanted devices from infections,” Dr. Tatara said.
