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Phage research offers promising solutions for global biosecurity, especially in combating antibiotic-resistant bacteria and emerging pathogens. Bacteriophages (viruses that infect bacteria) are being explored as alternatives to traditional antibiotics and as innovative vaccine platforms. This is particularly relevant in resource-limited settings, where phage-based technologies' adaptability, scalability, and cost-effectiveness can provide significant advantages. Developing phage vaccines could improve pandemic preparedness, reduce vaccine costs, and enhance health security in vulnerable regions, making phage technology a crucial tool for future global health strategies.
Background
Global catastrophic biological risks are something that could threaten the long-term flourishing of human civilisation and could impair our ability to have a long, really big future full of joy and flourishing for many different sentient beings (https://www.effectivealtruism.org/articles/biosecurity-as-an-ea-cause-area-claire-zabel). Based on the above definition, anything that can affect or hamper our future full of Joy threatens our existence. Several approaches are being proposed and adopted to secure our long-term existence on Earth. This piece will analyse phages' role in global biosecurity measures, particularly in resource-limited settings.
Bacteriophages, viruses that infect bacteria, are composed of genetic material (either DNA or RNA, in single or double strands) encased in a protein shell called a capsid. These viruses infiltrate bacterial cells by introducing their nucleic acids into the host. Once inside, bacteriophages follow one of two paths: they either replicate rapidly, causing the host cell to burst (lysis), integrate into the bacterial genome or exist as separate plasmids, becoming dormant prophages. They play crucial roles in genomic evolutions, driving bacteria virulence through gene transfers.
Bacteriophages have emerged as versatile tools in biotechnology and medicine, offering numerous applications. They serve as promising alternatives to traditional antibiotics, potentially addressing the growing concern of antibiotic resistance. In research, bacteriophages are efficient tools for screening vast libraries of proteins, peptides, or antibodies, accelerating drug discovery and development. The medical field harnesses bacteriophages as vectors for protein and DNA vaccines, enhancing immunisation strategies. Additionally, these bacterial viruses show potential as delivery vehicles in gene therapy, offering a novel approach to treating genetic disorders by precisely targeting specific cells.
Phage Research for Pandemic Preparedness:
COVID-19 caused a global economic impact in an unprecedented manner that may continue for years. Across countries, gross domestic product (GDP) fell by 2–4% in 2020, and the US had the worst contraction in national GDP since World War II. Despite major economic shocks, the economic burden of the pandemic may have been worse if not for at least some prior spending on pandemic preparedness and response tactics. For example, the US National Institutes of Health (NIH) spent $17.2 billion in vaccine technology research—more than $500 million toward mRNA, virus-like particle, and nanoparticle vaccines— before 2020 with specific attention to diseases with pandemic potential(1). These early initiatives set some foundational work on which new COVID-19 vaccine candidates were based.
During a pandemic, we need a fast way and cheap way to create solutions such as a vaccine. Because vaccine development is a complex process, vaccine vehicle studies should be encouraged. Some traits that make phage vaccines good tools include the fact that the phage genome is highly adaptable, allowing for the display of antigens or the creation of DNA vaccines. Phages are relatively easy to produce at scale, significantly reducing manufacturing costs. Their stability across diverse environmental conditions makes them ideal for efficient transport and storage. Phages are excellent vaccine tools for protein and epitope immunisation. Bacteriophage systems have been adapted as therapeutic and diagnostic platforms (2), and phage-like particles (PLPs) derived from phage capsid proteins are employed as scaffolds for genetic and chemical modification. Phages and PLPs have also been used as vaccine platforms to display antigens, including Y. pestis(3), P. falciparum(4), and recently SARS-CoV-2(5). Despite extensive enticing pre-clinical data supporting phage vaccines, these approaches have yet to be widely adopted, and no phage vaccines are currently FDA-approved.
Cost-effectiveness of phage vaccine using Typhoid fever
To estimate the cost-effectiveness of the phage vaccine, we adopt Typhoid, an endemic disease in Nigeria. The goal is to compare this novel vaccine approach's financial and health impacts with existing typhoid conjugate vaccines (TCVs), using key metrics such as Disability-Adjusted Life Years (DALYs) and overall project costs.
Assumptions and Data Sources
The analysis draws on several core assumptions based on current data:
Typhoid Incidence: An estimated 9.24 million cases of typhoid occur annually (WHO, 2022).
Mortality Rate: Approximately 1% of these cases result in death, contributing to 110,000 deaths globally per year.(6)
Disability-Adjusted Life Years (DALYs): The burden of typhoid in terms of DALYs is estimated at 0.11 per case
Vaccine Efficacy: Current TCVs show an efficacy of 84% in the first year, which declines to 50% by year five(7). The projected efficacy of the phage-based vaccine is assumed to be 90% over five years.
Vaccine Costs: The production cost of the current TCVs is $3 per dose, while the phage-based vaccine is estimated at $2 per dose. The cost of vaccine administration is estimated at $1 per dose for both vaccines.
Development Costs: The total estimated project development cost for the phage-based vaccine is $1.5 million
Target Population: The study targets a population of 10 million people living in high-risk areas for typhoid fever.
Cost Analysis
The cost analysis considers both the development and implementation costs for vaccinating 10 million people.
Development Costs: The phage-based vaccine development is projected to cost $1.5 million.
Implementation Costs: The total cost for vaccinating the target population with the current TCV would be $40 million, while the phage-based vaccine would cost $30 million.
Thus, the total cost of developing and implementing the phage-based vaccine is $31.5 million.
Effectiveness Analysis
The effectiveness of both vaccines is assessed in terms of DALYs averted.
Annual Typhoid Cases: In the target population, an estimated 100,000 cases of typhoid occur annually.
DALYs without Vaccination: These cases result in a total burden of 11,000 DALYs annually (100,000 × 0.11).
DALYs with Vaccination: The current TCV, with an 84% efficacy rate, reduces the DALYs to 1,760 per year. With the phage-based vaccine, at a 90% efficacy rate, the DALYs would be reduced to 1,100 annually.
DALYs Averted Over Five Years: The current TCV would avert 46,200 DALYs over five years, while the phage-based vaccine would avert 49,500 DALYs.
Cost-Effectiveness Ratio
The cost-effectiveness of each vaccine is calculated based on the cost per DALY averted.
Current TCV: The cost per DALY averted with the current TCV is $866.
Phage-Based Vaccine: The cost per DALY averted with the phage-based vaccine is $636.
Additional Benefits
In addition to cost-effectiveness, the phage-based vaccine offers several practical benefits:
Ambient Temperature Stability: The phage-based vaccine's stability at ambient temperatures could reduce cold chain costs by an estimated 20%.
Longer-Lasting Efficacy: The phage-based vaccine’s more prolonged duration of efficacy could reduce the need for frequent booster doses.
Local Production Capacity: Developing local production facilities for the phage-based vaccine would enhance pandemic preparedness and reduce reliance on imports, boosting regional health security.
A phage-based typhoid vaccine presents significant cost-effectiveness advantages over the current TCVs. The phage-based approach offers a promising alternative with a lower cost per DALY averted ($636 vs $866) and a higher number of DALYs averted over five years (49,500 vs 46,200).
Additionally, the vaccine’s ambient temperature stability, potential for fewer boosters, and prospects for local production further enhance its appeal, particularly in resource-limited settings. These findings support further investment in phage-based vaccine development as a more efficient and sustainable strategy for combating typhoid fever in vulnerable populations.
Phage Research in Resource limited Setting: Lessons from my lab
Phage research has grown recently with the growing threat of antimicrobial resistance. Much attention has been paid to phage development as an alternative to antibiotics. In resource-limited settings like Nigeria, interestingly, Phage research interest is also growing. This can be seen across Africa also. Some of the reasons for this growth can be attributed to:
The Ease of doing phage research: You can isolate any phage with just a shaker incubator, membrane filter, and bacteriological media. A phage lab does not require a high level of sophistication.
Abundance of environmental sources: Our environment's poor sanitary conditions are partly an advantage; they serve as a rich source of phages.
Easy way to impact: One easy way to impact is through phage research. Drug development for agricultural and human use is quite expensive and may be out of reach for an introductory lab in Nigeria. But with Phages, I can isolate phages for any bacteria of local relevance and get close to pre-clinical trials quite early and quickly.
Conclusion:
The hesitancy towards using bacteriophages in medical applications should be reconsidered in light of their role. However, several challenges remain in developing phage-based vaccines and treatments. These include the limited number of clinical trials, concerns about endotoxin contamination in phage preparations, the complexity of phage composition, and the need for long-term studies to assess any potential adverse effects. Addressing these issues through rigorous research and regulatory processes could pave the way for the responsible development of phage-based medical interventions.
References
- Kiszewski AE, Cleary EG, Jackson MJ, Ledley FD. NIH funding for vaccine readiness before the COVID-19 pandemic. Vaccine. 2021;39(17):2458-66.
- Bakhshinejad B, Sadeghizadeh M. Bacteriophages and their applications in the diagnosis and treatment of hepatitis B virus infection. World Journal of Gastroenterology: WJG. 2014;20(33):11671.
- Tao P, Mahalingam M, Rao VB. Highly effective soluble and bacteriophage T4 nanoparticle plague vaccines against Yersinia pestis. Vaccine Design: Methods and Protocols: Volume 1: Vaccines for Human Diseases. 2016:499-518.
- Palma M. Epitopes and mimotopes identification using phage display for vaccine development against infectious pathogens. Vaccines. 2023;11(7):1176.
- Zhu J, Ananthaswamy N, Jain S, Batra H, Tang W-C, Lewry DA, et al. A universal bacteriophage T4 nanoparticle platform to design multiplex SARS-CoV-2 vaccine candidates by CRISPR engineering. Science advances. 2021;7(37):eabh1547.
- Gibani MM, Jones E, Barton A, Jin C, Meek J, Camara S, et al. Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model. Nature medicine. 2019;25(7):1082-8.
- Shakya M, Colin-Jones R, Theiss-Nyland K, Voysey M, Pant D, Smith N, et al. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. New England Journal of Medicine. 2019;381(23):2209-18.