In conversation with

Dr. Irfan Qayoom

on his recent publication

Anti-infective composite cryogel scaffold treats osteomyelitis and augments bone healing in rat femoral condyle. Qayoom I, Srivastava E, Kumar A. Biomaterials Advances. 2022 Nov 1;142:213133.

MFCEM First and foremost, congratulations on your recent publication; could you share with us what need does the study address?

Dr. Irfan Qayoom: I would like to thank you on behalf of all authors for reaching to us and appreciating the work done by our team. In this study, we have tried to develop an improvised approach so as to improve the current clinical treatment strategies that are used to manage and treat osteomyelitis and related complications. The current clinical treatment modalities utilized to treat osteomyelitis infections are associated with enormous limitations which include lower bioavailability of antibiotic at the infectious site, off the target comorbidities, and secondary complications like fractures and amputations. We have hereby developed a biomimetic local antibiotic delivery system from biocompatible and osteo-active biomaterials, collagen and nanohydroxyapatite using cryogelation to clear the infection and at the same time enhance the bone formation at the debrided site created during surgical procedures.

MFCEM How is your approach distinct from the existing ones; does the use of an inorganic-organic composite gel engineered in this study provide a distinct advantage over others?

Dr. Irfan Qayoom: The development of porous composite cryogel as an antibiotic delivery system provides advantage of using in large sized bone infectious lesions. The commercially available polymethylmethacrylate (PMMA) beads used to clear the infection has several disadvantages like PMMA is bioinert, has dysregulated antibiotic release profile and most importantly is non-porous which does not allow proper gaseous and nutritious exchange thereby causing anoxic injuries eventually leading to infection related complications. Our porous composite cryogel system is macroporous system which is osteoactive, show controlled antibiotic release and allows ambient gaseous and nutritious exchange thus enhancing the infiltration of immune cells and other osteoprogenitor cells to clear the infection and simultaneously, enhance the bone formation at the infectious lesions.

MFCEM In this study you have also made use of mathematical modelling to calculate the antibiotic release rate from the scaffold; did this allow you to transcend the experimental limitations?

Dr. Irfan Qayoom: In this study we have used mathematical modelling to support our experimental data that our system shows sustained release kinetics at physiological pH. It was observed that at physiological pH, the release kinetics follows a model that is fit for long-term release of antibiotic and will ensure the availability of antibiotic at the infectious lesion to clear infection completely and also prevent the formation of biofilm by the persister bacterial cells.

MFCEM What was the major challenge you faced while engineering the cryogel scaffold? How did you overcome it?

Dr. Irfan Qayoom: The major challenge was the synthesis and fabrication of porous composite cryogels itself with both organic and inorganic components. The synthesis of cryogel was optimized with multiple methods so that it contains optimum concentration of inorganic nanohydroxyapatite till we developed a new and modified method to synthesize an antibiotic loaded-biomimetic cryogel scaffolds with compositional and structural resemblance to the natural trabecular bone.

MFCEM Are you contemplating a technology transfer for scaling purposes in the near future?

Dr. Irfan Qayoom: The potential of our nanohydroxyapatite based antibiotic carriers have already been recognized by DBT-BIRAC and funded under BIG grant wherein we have started a startup if “REGENMEDICA PRIVATE LIMITED” to develop a prototype of the product that will be further commercialized for clinical applications in bone and spinal tuberculosis infections.

In conversation with First Author, Namrata Baruah

On her recent publication

Stable Recombinant Invasion Plasmid Antigen C (IpaC)-Based Single Dose Nanovaccine for Shigellosis. Baruah N, Halder P, Koley H, Katti DS. Mol Pharm. 2022.

MFCEM: Congratulations on this publication. It follows your previous study on Ipa-based nasal vaccine for Shigellosis. What was the motivation to engineer this vaccine and further improvise it?

Namrata Baruah: Thank you! This is year 2022 and hundreds of people are still dying due to shigellosis- a diarrheal disease, for which a commercial vaccine is unfortunately, not available. The situation is grim because most strains of Shigella, the bacterial pathogen, have become multi-drug resistant. There may soon be an outbreak we do not have antibiotics for. Therefore, the requirement of a vaccine is paramount.

Although there have been considerable research, a vaccine passing all the phases of clinical trials is still not available mainly because of low immunogenicity of the antigen(s) or serotype specific narrow-range protection of the vaccine candidates. Instability of immunogenic, potential vaccine antigens, exacerbates the problem. Therefore, we first stabilized a potential immunogen –IpaC, a protein found in all Shigella strains. We then assessed its vaccine potential with the available resources, and surprisingly found it to be cross-protective (heterologous protection) without any adjuvant. To further reduce dosing and increase eventual patient compliance, we encapsulated the minimum protective amount of the stabilized protein into PLGA (polymer with several FDA approved applications) nanoparticles to obtain a minimalistic single dose nanovaccine for shigellosis which is expected to protect against all Shigella strains.

MFCEM: Can you explain for the larger scientific community the technology used to develop this vaccine. How do the improvisations implemented by you push the field of vaccine development forward?

Namrata Baruah: To develop the nanovaccine, we first stabilized an immunogenic recombinant Shigella protein-IpaC (origin- Shigella dysenteriae 1, the most harmful Shigella with the most unstable IpaC) which resulted in a self-adjuvanting single-antigen nasal vaccine. Nasal immunization can provide protection at a different site such as the intestine because of the common mucosal immune system (CMIS).

 Further, compared to oral, nasal vaccines provide higher protection with lesser dose and thus, most Shigella vaccine candidates currently being explored are intranasally administered. The stabilized IpaC vaccine could protect the immunized mice against a high dose challenge of a heterologous Shigella (S. flexneri 2a, the most common type around the globe) whereas, all the unimmunized control mice died after severe diarrhea. Therefore, we obtained a cross-protective vaccine. Cross-protection against Shigella dysenteriae is difficult to achieve and there are only few reports showing minimal protection. Therefore, we chose IpaC protein of S. dysenteriae origin (most vaccine candidates currently being explored are from S. flexneri origin), as it is bound to show homologous protection. Therefore, as expected, it protected immunized mice from bloody diarrhea. However, the vaccine needed to be administered in 3 doses which meant that eventually, patients would be required to visit a hospital or care facility for 3 times at regular intervals. As the disease mainly affects the infants and the elderly, decreasing hospital visits was a priority. Therefore, we explored a single-dose nasal vaccine. As biodegradable polymeric nanoparticles are known to show a depot effect leading to slow release of the encapsulants, we chose a nanoparticle system which was expected to result in greater circulation time of the stabilized IpaC in the body and hence, equivalent immunogenicity at 1/3^rd the dose. We chose the biodegradable polymer PLGA with established safety (FDA approved for multiple applications) as it is expected to shorten the entire process of lab to the market.

Since, the current vaccine candidate is a single antigen, single dose, cross-protective, facile formulation, therefore, our work should accelerate the progress towards a protective commercial Shigella vaccine.

MFCEM: Could you comment on the possibility of translating this technique for developing vaccines for human use. Do you envisage it happening in the near future?

Namrata Baruah: The minimalistic, cross-protective, single dose nanovaccine is amenable to translation at a large scale because of the following reasons-

First, being recombinant, IpaC protein purification omits pathogenic Shigella culture requiring a BSL 2 facility. Second, the stabilized IpaC protein was found to be stable at a multitude of temperatures, which would ultimately reduce the cost of storage and/or transportation of the protein. Third, the nanovaccine is minimalistic requiring only a few elements to complete the whole process after which it can be lyophilized and stored for years at room temperature. Fourth, as it is an intranasal vaccine, trained personnels for vaccine administration would not be required. Finally, due to a single dose, it is expected to increase patient compliance and overall acceptance. All of these factors can reduce cost and effort and therefore, after rigorous testing, I expect the nanovaccine to at least be part of the solution especially in low and middle income countries where the disease causes greater harm.