Biomaterial vaccines prevent a wide range of bacterial infections and septic shock

Current clinical interventions for infectious diseases face increasing challenges due to the growing number of drug-resistant microbial infections, epidemic outbreaks of pathogenic bacteria, and the continuing possibility of new biotherapeutic threats that may arise in the future. Effective vaccines could act as a bulwark to prevent many bacterial infections and some of their most serious consequences, including sepsis. According to the Centers for Disease Control and Prevention (CDC), “Every year, at least 1.7 million adults in America develop sepsis. About 270,000 Americans die as a result of sepsis. [and] 1 in 3 patients who die in a hospital has sepsis. “However, for the most common bacterial pathogens that cause sepsis and many other diseases, vaccines are not yet available.

Now, as reported in Biomedical Engineering of Nature, a multidisciplinary team of researchers from the Harys Institute of Biologically Inspired Engineering at Wyss and the John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed an infection-based vaccine approach based on biomaterials (ciVAX) as a solution that could be broadly applied to this widespread problem. CiVAX vaccines combine two technologies that are currently in clinical development for other applications and that, together, allow the capture of immunogenic antigens from a wide spectrum of pathogens and their incorporation into biomaterial scaffolds for immune cell recruitment. . Injected or implanted under the skin, ciVAX vaccines reprogram the immune system to act against pathogens.

“The protective powers of the vaccines we have designed and tested so far and the immune responses they have stimulated are extremely encouraging and open up a wide range of potential vaccine applications ranging from sepsis prophylaxis to rapid measures against future ones. pandemic and biomedical threats, as well as new solutions to some of the challenges of veterinary medicine, ”said the corresponding author, David Mooney, Ph.D., a founding member of the Wyss Institute’s basic faculty and who leads the platform Immuno-Materials Institute. He is also a professor of bioengineering for the Robert P. Pinkas family at SEAS.

In their study, researchers successfully tested ciVAX technology as a measure of protection against the most common causes of sepsis, including Gram-positive S. aureus strains and Gram-negative E. strains. Highlighting the potential of the technology, they found that a ciVAX prophylactic vaccine protected all vaccinated mice from a lethal attack with an antibiotic-resistant E. coli strain, while only 9% of unvaccinated control animals survived. In a model of septic shock pig induced by an isolate other than E. Human coli, a ciVAX vaccine prevented the development of sepsis in all four animals, while four unvaccinated animals developed severe and sudden sepsis within 12 hours. Finally, through an approach that mimicked an annular vaccination protocol in human or animal populations, a ciVax vaccine, loaded with material derived from pathogens isolated from animals infected with a lethal strain of E. coli. Coli, was able to cross-protect animals from E.’s lethal strain. coli.

“Our method captures most glycoprotein (and glycolipid) antigens from pathogens and presents them in their native form to the immune system, giving us access to a much larger potential antigen spectrum than vaccines that consist of in individual recombinant antigens or mixtures, ”said Wyss co-author and lead scientist Michael Super, Ph.D. “CiVAX vaccines against known pathogens can be manufactured and stored, but in addition, all components, except bacterial antigens, can be pre-assembled from platform-stable cGMP products. Complete vaccines can be assembled in less than ‘one hour once the antigens are available, which provides this technology with unique advantages over other vaccine approaches when rapid responses are required.’ Super conceived the ciVAX concept with co-author Edward Doherty, who as a lead scientist worked with Mooney on Wyss ’Immuno-Material platform on biomaterial-based vaccines for cancer applications.

The founding director of Super and Wyss, Donald Ingber, MD, Ph.D., who was also the author of the study, previously developed the pathogen capture technology used in ciVAX, which is based on a native opsonin that binds to the human pathogen — mannose-binding lectin (MBL) —which fused to the Fc portion of an immunoglobulin to generate FcMBL. Recombinant FcMBL binds to more than 120 different pathogenic species and toxins, including bacteria, fungi, viruses, and parasites. In previous efforts, the team applied FcMBL to multiple diagnostic problems and the technology is currently being tested in a clinical trial by the start of Wyss BOA Biomedical as part of a new sepsis treatment.

The second technological component of the ciVAX component, the biomaterial-based vaccine technology, was developed as a conceptually new type of cancer immunotherapy by Mooney and his group at the Wyss Institute and SEAS, along with clinical collaborators from the Dana-Farber Cancer Institute. Validated in a clinical trial in human cancer patients, a specifically designed cancer vaccine stimulated important antitumor immune responses. Novartis is currently working to commercialize vaccine technology for certain cancer applications and Wyss startup Attivare Therapeutics is pursuing a biomaterial-based vaccine-related approach, with Doherty researchers and former Wyss researcher Benjamin Seiler and Fernanda Langellotto, Ph.D. he was also a co-author of this study, as a founding member.

To assemble the ciVAX vaccines, the team used FcMBL in magnetic beads to capture inactivated bacterial molecules containing carbohydrates, known as Pathogen Associated Molecular Patterns (PAMP), from the chosen pathogen, and then simply mixed the complexes. with mesoporous silica particles (MPS)) and immune cell activation and recruitment factors. Under the skin, MPS forms a permeable, biodegradable scaffold that recruits dendritic (DC) cells from the immune system, reprograms them to present fragments of the captured PAMPs, and releases them again. DCs then migrate to nearby draining lymph nodes where they orchestrate a broad immune response against the bacterial pathogen. The team found that ciVAX vaccines rapidly improved DC accumulation and activation at injection sites and the number of DCs, antibody-producing B cells, and different types of T cells in the lymph nodes. draining and therefore designed effective immune responses targeted by pathogens.

“Beyond the potential to reduce the risk of sepsis inside and outside hospitals, our ciVAX vaccine the technology has the potential to save the lives of many individuals threatened by a multitude of pathogens, as well as potentially prevent the spread of infections to animal or livestock populations before they reach humans. It’s a fantastic example of how Wyss researchers from different disciplines and experiences come together around medical problems that need to be solved urgently to create powerful new approaches, ”said Ingber, who is also a professor of vascular biology at Judah Folkman in l ‘HMS and Boston Children’s Hospital and Professor of Bioengineering at Harvard John A. Paulson School of Engineering and Applied Sciences.