With the mounting number of drug-resistant microbial infections, the epidemic outbreak of pathogenic bacteria, and the possible threat of new organisms in the future, the clinical intervention of infectious diseases is facing increasing challenges. Effective vaccines can be used as a barrier against many bacterial infections and their serious consequences, including sepsis. However, there is still no vaccine available for the common bacterial pathogens that cause sepsis and many other diseases.
In order to meet this challenge, a multidisciplinary research team from WyssInstitute for Biological Inspired Engineering and John A. Paulson from School of Engineering and Applied Sciences (SEAS) at Harvard University recently developed a broad-spectrum anti-infective vaccine ciVAX based on biomaterials. The vaccine combines two techniques to capture immunogenic antigens from broad-spectrum pathogens and incorporate them into immune cell recruitment biomaterial scaffolds. When ciVAX is injected or implanted under the skin, the vaccine reprograms the immune system against pathogens.
CiVAX’s strong immunogenicity, low incidence of adverse events, and modular production process make it a potential tool to deal with bacterial epidemics and biological threats. The relevant research results were published in Nature Biomedical Engineering.
Dual technology used
The lead author, Dr. Michael Super, and Wyss’s founding director, Dr. Donald Ingber, had previously developed the pathogen capture technique used in ciVAX, which is based on the natural human pathogen-binding modulin, mannose-binding lectin (MBL) that fuses into the Fc portion of immunoglobulin to produce FcMBL. Recombinant FcMBL can bind to more than 120 different pathogens and toxins, including bacteria, fungi, viruses, and parasites.
The second technical component of ciVAX is biomaterial-based vaccine technology, a conceptual new type of cancer immunotherapy developed by Dr. David Mooney, who led the study and his team with clinical collaborators at the Dana Farber Cancer Institute. The treatment has been validated in clinical trials of cancer patients and studies showed that a specially designed cancer vaccine can stimulate a significant anti-tumor immune response. Novartis is currently working on commercializing the vaccine technology for some cancer treatments.
To assemble the ciVAX vaccine, the team used FcMBL-coated magnetic microspheres to capture the surface molecules (PAMP) of carbohydrate-containing compounds that inactivate bacteria, and then mixed the complex with mesoporous silica (MPS) particles, immune cell recruitment, and activators to form a complete ciVax vaccine.
After subcutaneous injection in mice, MPS formed a permeable and biodegradable scaffold that can recruit immature dendritic cells (DCs) from the immune system and reprogrammed them to present captured PAMP-derived antigens and reactivate and release them. These DC then migrated to the lymph nodes in the drainage area, where they produced a wide range of immune responses against bacterial pathogens.
The team found that ciVAX vaccine can rapidly enhance the accumulation and activation of DCs at the injection site, and increase the number of DCs, antibody-producing B cells and different types of T cells in the drainage area of the Lymph node, resulting in an effective pathogen-guided immune response.
The technology is modular and is ideal for producing ciVAX against new pathogens, and only the PAMP parts from inactivated pathogens need to be exchanged. CiVAX can even be used for vaccination with antigens captured and inactivated directly from infected animals, so it can be used quickly in the case of epidemics, zoonotic diseases, and unknown biological threats.
Dr Michael Super explained, “our approach is to capture most of the glycoprotein and glycolipid antigens from pathogens and present them to the immune system in the form of native, enabling us to obtain a larger potential antigenic spectrum than recombinant vaccines consisting of single or mixed antigens. In addition, ciVAX vaccines against known pathogens can be manufactured and stored, and all ingredients except bacterial antigens can be pre-assembled from available products in line with Current Good Manufacturing Practice regulations (cGMP). Once the antigen is available, the complete vaccine can be assembled in less than an hour, giving the technology a unique advantage over other vaccine methods when a rapid response is needed.”
Remarkable animal experiment result
In order to explore the potential of this technology, the researchers conducted a series of in vivo animal experiments. They found that prophylactic ciVAX vaccines protected all vaccinated mice from lethal attacks by antibiotic-resistant E. coli strains, while only 9% of unvaccinated mice survived.
In septic shock pig models induced by different human E. coli isolates, ciVAX vaccine prevented sepsis in all 4 model pigs, while severe and sudden sepsis occurred in 4 unvaccinated model pigs within 12 hours.
Finally, using a method that simulates a “circular” vaccination regimen in a human or animal population, ciVax vaccines can cross-protect animals from different lethal E. coli strains when loaded with pathogen-derived materials isolated from animals infected with a lethal E. coli strain.