Bending the AMR curve: The role of Vaccines, Biotherapeutics, and other preventatives
AMR — Is the global public health system ready for the next pandemic?
The COVID-19 pandemic has highlighted the public health challenges that an evolving virus with high transmissibility and infectivity can pose globally. Imagine a situation with multiple variants of different microbes circulating simultaneously, some resistant to known drugs and antibiotics! This is not a doomsday prophecy but a medical challenge in patient care being increasingly observed today. If this is not addressed now, it could lead to a vast public health challenge of antimicrobial resistance (AMR) in the coming years. Supporting and investing in preventive care can bend this curve by not just saving lives, but also a huge global economic burden.
The global economic burden would be devastating, costing approximately 100 trillion US dollars. According to WHO, 43 antibiotics in clinical development have already failed to address resistance among prevalent microbes. A study revealed that if AMR continues to escalate at present rates, by 2050 nearly 10 million deaths would occur annually, with 2 million deaths predicted in India alone!
In India, antibiotic usage has increased by 30.64% per capita in the last decade. In 2020 alone, the total antibiotic consumed was 7676 million DDD [defined daily dosage] (State of the World’s Antibiotics in 2021 report).
Antibiotics can be life-saving, but when misused or overused without considering the appropriate guidelines, it is a threat. Overall, global antibiotic consumption is projected to rise by 67% by 2030, resulting in increased and often unnecessary drug pressure on microbes leading to the development of resistance. This would leave us with very limited treatment options, and a situation catastrophic in human and capital costs!
In May 2015, the World Health Assembly adopted the Global Action Plan (GAP) outlining 5 objectives to tackle AMR. The focus on administering infection prevention measures, and increasing investment in new vaccines, and other preventive interventions have been highlighted, among other priority areas. Thus, support and development of preventative strategies is urgently needed to reduce the burden of global AMR.
Preventative Approaches — some new, some old
Vaccines at the forefront
Every year 2–3 million deaths are averted through vaccine interventions, especially in low- and middle-income countries (LMICs) where healthcare infrastructure is sparse and fragmented. By preventing infections and disease progression, vaccines reduce the chances of microbes from spreading, evolving, and thereby developing resistance. Also, disease prevention leads to reduced antibiotics pressure in the community, inadvertently lowering the risk of AMR as well.
For almost 200 years, vaccines have restricted the spread of infections, even eradicating a few.
For instance, after introducing pneumococcal conjugate vaccine [PCV 7] nearly ~211,000 invasive pneumococcal disease cases have been prevented annually. Measles vaccination has prevented almost 33 million deaths in last two decades.
Traditionally viewed as a long and arduous process, involving the use of attenuated or killed microbes, or alternately culturing microbes and subsequently purifying the desired subunits, recent advancements in vaccine development have made it easier to fast-track identification of potential candidates and conduct the necessary clinical validations.
What’s new in the 21st Century Vaccine scenario?
· It is now possible to design immunogenic microbial subunits separately instead of first growing the microbes and then purifying the immunogenic components. This has brought down the cost and the time required for producing these at scale.
· Through Reverse vaccinology, potential antigen encoding genes can be selected and tested for vaccinesin invitro and in vivo preclinical trials. This approach has successfully produced Meningococcus B vaccine and that is in trial for vaccines against E. coli and P. aeruginosa.
· Traditionally, glycoconjugate vaccine manufacture involved extensive multi-step bio-chemical processes. Bioconjugation has now allowed glycoconjugate vaccine production through a single fermentation step using enzymes like oligosaccharyltransferases.
Biotherapeutics
Besides vaccines, biotherapeutics is an emerging preventive strategy.
Monoclonal antibodies [mAbs], bacteriophage, and microbiota-based strategies are promising approaches.
They are currently used to prevent reinfection with ongoing trials to stop incidences of primary infection. Mostly used in combination with standard-of care antibiotics to enhance efficacy.
Monoclonal antibodies bind to the pathogen surface and inhibit their activity with subsequent lysis through various mechanisms.
MAbs are favourable for immunocompromised or elderly people who may not have effective immune response from vaccines.
Currently, monoclonal antibodies against bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus anthracis, Clostridioides difficile, and Escherichia coli have been explored. Monoclonal antibodies can be given as a prophylactic treatment or combined with antibiotics as adjuvants. Bezlotoxumab, mAb against Clostridium difficile infection when given with standard care antibiotics significantly reduced the recurrence of infection.
Phage therapy uses lytic phages which selectively target pathogen and eliminate them. These are target-specific thereby minimising the disruption of gut microflora.
Phage Therapy is of particular interest to prevent and control biofilm-associated infections.
S. aureus and P.aeruginosa have been targeted for phage therapy. This could be used in synergy with existing antibiotic treatment. For example, when antibiotics and phage were combined against E.coli infection there was improved biofilm control on contrary to antibiotics alone. Also, phage cocktails when applied on dwelling devices like catheters can inhibit bacterial growth, thus preventing chances of infection.
C-CAMP supported startup, Gangagen’s proprietary PATP has been used to design novel lysin molecules against gram-positive and gram-negative bacteria. Their most developed molecule is against Staphylococci.
Microbiota-based interventions have been picking up in recent years, with an objective to reduce recurrence of infections particularly for C.difficile. Fecal microbiota transplant [FMT], spore formulations have been administered in patients with severe cases of infection leading to hospitalisation and significant results were seen with instances of clinical resolution achievement in few patients. CARB-X portfolio supports decolonization programs from both live-biotherapeutic and engineered-phage approaches. These aim to eradicate bad bacteria from the gut, thereby preventing breakthrough bloodstream infections.
The CARB-X Biotherapeutics portfolio
In the LBT arena, CARB-X’s graduate Vedanta is advancing development of a product for recurrent C. difficile with the support of BARDA; Vedanta also has a program currently in-portfolio focused on decolonization of carbapenem-resistant Enterobacteriaceae (CRE), and Seres has graduated recently to commence first-in-human studies with a consortium product focused on decolonization to prevent graft-versus-host disease and breakthrough infections in transplantation patients caused by CRE.
In the engineered-phage arena, Eligo is aimed at decolonizing ESBL+ and CRE+ organisms in transplantation patients, while SNIPR Biome is aimed at decolonizing E. coli in cancer patients with hematological malignancies.
Other Preventives
Immunomodulators are another option for secondary preventive treatment. Also, basic hygiene maintenance and sanitation in clinical and community settings can have a remarkable effect.
Following fundamental hygiene and sanitary practices can potentially prevent 9% of global infection burden.
Supporting upcoming preventative solutions: Foster and Grow
C-CAMP is a pioneer in the life-sciences entrepreneurship ecosystem in India that recognizes, fosters, incubates and promotes innovative solutions by early stage start-ups. C-CAMP has supported solutions across different domains in AMR, including preventatives. C-CAMP is the only organization outside USA & Europe that is part of CARB-X’s Global Accelerator Network (GAN) working towards combating anti-microbial resistance (AMR) by providing scientific, technical and business support to fast track the latest AMR related innovations and deep science technology. C-CAMP has partnered with CARB-X to further its impact in this domain. CARB-X, a non-profit partnership led by Boston University, supports various innovations in AMR, from vaccines to biotherapeutics. CARB-X is accelerating global antibacterial innovation by investing in the development of new antibiotics and other life-saving products to combat the most dangerous drug-resistant bacteria. Their project supports preventatives, among other domains in AMR.
Vaccine development: What are we doing?
Today, the CARB-X portfolio includes eight (8) individual projects focused on delivering novel AMR vaccines. Although the technologies, stages of development and teams progressing them vary, they cover several key pathogens highlighted on the CDC and WHO lists of threat bacteria.
Staphylococcus aureus: Affinivax, has designed a novel vaccine against Staph infections. Using their vaccine technology platform, Multiple Antigen-presenting System, they aim to prevent Staphylococcus aureus infections. Their innovative platform uses biotin-rhizavidin binding interaction which mounts powerful B-cell and T-cell responses within a single vaccine.
Integrated BioTherapeutics, based out of Maryland, USA, has designed 7 unique Staphylococcus aureus toxins containing vaccine-IBT-V02. This is the first non-surface antigen-based vaccine. Past vaccines used surface proteins that induced opsonic antibodies. Unfortunately, this approach hasn’t been very effective in human trials. IBT-V02 uses cytolytic and super antigenic toxins that provide strong protection against primary and recurrent skin infections.
Klebsiella pneumoniae: Vaxdyn has formulated a single trivalent vaccine against Gram-negative pathogens A.baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Another company developing multivalent conjugate vaccine is Idorsia. They are targeting 80% Carbapenam resistant strains of Klebsiella pneumoniae, one of the prominent superbugs.
Neisseria gonorrhoeae: Researchers of the Jenner Institute have developed a novel gonorrhea vaccine using novel outer membrane vesicles.
Salmonella enterica: Glaxo Ventures for Global Health (GSK Bio) GSK biologicals and its affiliate GSK Vaccines Institute for Global health [GVGH] are designing two novel vaccines against Salmonella enterica and for Group A streptococcus infections. In the dearth of a vaccines for either of these diseases, these could be instrumental in preventing the infections and reducing the mortality and burden of antibiotics. Currently, these are in the pre-clinical development phase.
Group A Streptococcus: Aside from GVGH, Vaxcyte is formulating a GAS [Group A Streptococcus] carbohydrate antigen vaccine to fight against pharyngitis infection as a result of Strep throat.
Medical Devices
C-CAMP supported start-up, Biomoneta, has developed Zebox to lower the spread of infection by trapping and killing airborne microbes within 20 mins.
Coeo Labs, a division of InnAccel technologies, on the other hand, are building an AI-based device ‘VAPCare’. This sensory device sucks out secretions from the oral pathway and reduces the chances of acquiring Ventilator-Associated Pneumonia to prevent ‘Ventilator-associated pneumonia’.
Immunotherapy
Seattle-based start-up Lumen Biosciences, supported by CARB-X, is developing an oral antibiotic alternative cocktail containing antibody-like protein biologics that neutralize the pathogens of Traveller’s diarrhoea; which is one of the leading causes of death in infants and children.
The road ahead
With no new antimicrobials expected to reach the market in the next two decades, there is an urgent need to broaden the base of potential interventions that would funnel through the development pipeline for AMR focused solutions.
Preventing infections is the starting point that can lower the loss and control the crisis.
Research and development in preventives need to be propelled further. Partnership at the academia and industry interface can help achieve this. Pharma companies must be incentivised to invest in exploring new and innovative technologies. A constant dialogue between Policy makers, Regulators and Public Health stakeholders is crucial in aiding the development of new technologies as well as helping in creating a robust market.
Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however this does not claim to be an exhaustive document on the subject. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.
