Phage Bank: A Promising Solution to Antimicrobial Resistance in Nigeria

Summary 

Antimicrobial resistance (AMR) is a major global health threat, and it is particularly acute in Nigeria. Phage therapy is a promising alternative to antibiotics for the treatment of AMR infections, but phage research in Africa is limited. Establishing a phage bank in Nigeria would provide a number of benefits. I have attempted to provide my perspective on why I feel a Phage Bank is important and why Phage Bank is a viable alternative in the fight against AMR in Nigeria

Background

Phage banks are repositories that store and preserve collections of bacteriophages, which are viruses that infect and kill bacteria. They have the potential to be utilized in place of or in addition to antibiotic therapy when treating bacterial infections. Phages have shown potential as an alternative to traditional antibiotics in treating bacterial infections, including those caused by antibiotic-resistant bacteria. By using phages, researchers and healthcare professionals aim to combat the growing problem of antimicrobial resistance.

In the wake of the COVID-19 Pandemic, low and medium-income(LMIC) countries depended mostly on the western countries for the supply of vaccines, medicines and laboratory support to be able to respond to COVID-19. There were lots of delays. The WHO released a statement on the state of vaccination globally saying that “ More than 6.4 billion vaccine doses have now been administered globally, and almost one-third of the world’s population is fully vaccinated against COVID-19. But those numbers mask a horrifying inequity. Low-income countries have received less than half of one percent of the world’s vaccines. In Africa, less than 5% of people are fully vaccinated.”  Vaccine inequality became obvious leaving the African population begging for supplies. This is partly because we lack the capacity for vaccine production and to prepare for pandemics.

Importance:

According to a recent publication on the global burden of bacteria resistance. There were an estimated 4·95 million (3·62–6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial AMR. At the regional level, it was estimated the all-age death rate attributable to resistance is highest in western sub-Saharan Africa((23.5 deaths per 100,000) attributable to AMR compared to other regions.)

All-age rate of deaths attributable to and associated with bacterial antimicrobial resistance by GBD region, 2019

Western Sub-Saharan Africa (SSA) where Nigeria belongs bears the highest burden of drug resistance death.  It  is estimated that by 2050, mortalities attributed to AMR will have increased to 10 million annually with Africa and South Asia bearing the highest burden of deaths. The problem of AMR is real and a big issue in SSA

Neglectedness:

Prevailing high levels of poverty, poor regulation of antimicrobial use, and a lack of alternatives to ineffective antimicrobials have been identified as the cause of high death rates from AMR in SSA. Phages are a good alternative to management of AMRs.

Timeline showing an increase in Phage research(source)

Phage therapy is defined as the administration of virulent phages directly to a patient with the purpose of lysing the bacterial pathogen that is causing a clinically relevant infection. The 1940s can be considered the golden age of antibiotics production with more than 40 antibiotics being discovered and introduced for clinical use. However, since 1990 no new antibiotics have been developed. The majority of recently introduced antibiotics are either modified or combined versions of previously known compounds. It is estimated that only five out of 5,000 to 10,000 candidate molecules reach phase I studies and that only one out of those five receives regulatory approval for human use. This has caused an increase in research on alternatives to antibiotics such as phage.

Phage research in Africa is abysmally low. 

Map showing the distribution of Phage researchers across Africa( This chart shows members of the African Phage Forum (APF) https://africaphageforum.org/

A number of countries have established phage banks to prepare for antimicrobial resistance.  The longest-standing of those include the Felix d'Herelle Reference Center for Bacterial Viruses in Canada (>400 phages), the American Type Culture Collection (ATCC) in the US (∼350 phages), the German Collection of Microorganisms and Cell Cultures (also known as DSMZ; with ∼450 phages), the National Collection of Type Cultures (NCTC) in the UK (>100 phages), and the Bacteriophage Bank of Korea (>1000 phages). However, no phage bank exists in Africa. 

As interest in phage research grows in Africa, phages that are clean, well-characterized, sequenced, and have a known host specificity Still needs to be documented. Currently, characterization, purification, sequencing, and storage of a single phage can be accomplished for under EUR 500. This is not at the moment realizable in Africa due to paucity of funds. So far, there is no single center in Africa serving as a manufacturing hub for bacteriophage.

Tractability: 

In 2019, a 7-year-old Dhanvi was involved in a car accident Her leg was about to be amputated due to an infection that antibiotics failed to cure. To find phages for Dhanvi, the team put out a call to phage researchers globally. A dozen labs volunteered to help, from all over the world. Samples of the bacteria from Dhanvi’s leg were sent to them. Each lab tested whether any of the phages in their collections could kill Dhanvi’s bacteria. Finally,  a research lab in Israel emailed back. They had found a phage that could kill her bacteria. Luckily, the lab had already studied that phage, and knew it was a good one. It didn’t have any harmful-looking genes, meaning it should be safe to use.

This is a classical example of how a phage bank can make an impact. A phage bank in Nigeria will serve people across the globe. 

The steps to testing a phage against a patient’s bacteria

Is starting a phage bank in Nigeria a realistic thing to do?

This question is sure to be on the lips of everyone reading this post. My first response will be Yes! It is realistic to start a phage bank in Nigeria. What are the major things needed for a phage bank to be successful? A phage bank should be able to isolate phages, purify phages and store them for anyone that may need them. Last year, I received one-time funding from Emergent Ventures to kickstart the process of a phage bank in Nigeria. First, we needed to sort out the issue of infrastructure and put in place the necessary equipment needed for phage studies. With the funds, we set up a facility that has the capacity to isolate phages and store phages. Two aspects we are yet to improve due to funds are solar energy for solving electricity challenges which will solve storage problems for the -80^oC freezer, and consumables for sequencing(This is necessary to determine the therapeutic potential of the phage). Students have started isolating phages in the lab, and so far we sequence our phages in collaboration with other labs.  In the sense of upgrading the lab to ensure storage and consumables for sequencing, yes, a phage bank is realistic in Nigeria.

How a Phage bank could be Used to treat antibiotic-resistant Infections in Nigeria A model 

• Establishment of a Phage Bank: Create a dedicated facility or collaborate with existing research institutions to establish a phage bank in Nigeria. The Phage Bank should have an active and robust collaboration with local hospitals, research centers, and universities to collect and isolate phages from various sources, including patients, sewage, and environmental samples. It should be able to implement a robust protocol for phage isolation, purification, and characterization to ensure the quality and safety of phages in the bank.
• Phage Characterization and Database: The Phage bank should conduct a comprehensive characterization of isolated phages, including their host range, efficacy against specific antibiotic-resistant bacteria, and safety profiles. The bank should develop a comprehensive database that includes information on each phage, such as its genetic sequence, target bacteria, and known therapeutic applications and implement a system to regularly update and maintain the database with new phages and their associated information.
• Collaboration and Networking: The Phage Bank should foster collaboration with local healthcare institutions, clinicians, and researchers to raise awareness and promote the use of phage therapy as a treatment option for antibiotic-resistant infections. It also ahsoul establish partnerships with regulatory bodies, such as NAFDAC, to navigate the approval process and ensure compliance with regulatory guidelines. Collaborate with international phage banks and research institutions to exchange knowledge, share resources, and access a broader range of phages.
• Clinical Trials and Treatment Guidelines: Conduct well-designed clinical trials to evaluate the safety and efficacy of phage therapy for different antibiotic-resistant infections prevalent in Nigeria. Develop treatment guidelines and protocols based on the outcomes of clinical trials, considering factors such as dosage, administration routes, and patient selection criteria. Educate healthcare professionals about the appropriate use of phage therapy, including proper patient selection, phage administration, and monitoring of treatment outcomes.
• Treatment Access and Distribution: Establish mechanisms for patients and healthcare providers to access phage therapy from the phage bank. Develop a streamlined process for matching patients with appropriate phages based on bacterial strain identification and phage database information. Ensure proper storage, quality control, and distribution of phage preparations to healthcare facilities across Nigeria.
• Surveillance and Research: Implement a surveillance system to monitor the prevalence of antibiotic-resistant bacteria and identify emerging strains or patterns of resistance. Conduct ongoing research to continuously expand the phage bank by isolating new phages, characterizing their properties, and updating the database accordingly. Collaborate with local and international researchers to investigate the mechanisms of phage-host interactions, phage resistance, and optimization of phage therapy protocols.

What are the barriers to starting and implementing a phage bank in Nigeria?

I would divide the barrier into the following:

Policy:

Phage treatment is not currently supported by any policies in Nigeria. The absence of a suitable legal and regulatory framework is the biggest barrier to the adoption of phage therapy in Western medicine and anywhere else in the globe. A practical framework for phage therapy is currently being implemented in Belgium, and it is focused on the magistral preparation (compounding pharmacy in the US) of specialized phage medications (https://pubmed.ncbi.nlm.nih.gov/29415431/). Magistral preparation is allowed in Nigeria. This we intend to explore for phage therapy. 

In 2022, The National Center for disease control(NCDC), the Federal Ministry of Health, and the Federal Ministry of the Environment which forms the Antimicrobial technical working group for Nigeria organized the 2022 National Antimicrobial Awareness Week (NAAW), I was invited as the guest speaker to talk to the nation on Phage therapy: A game changer in the AMR response space. In Nigeria, moves have already begun to allow for phage use in the treatment of persons. 

Funding:

Funding is a problem everywhere. However, a functional phage lab can be self-sustaining.  Just recently, Adaptive Therapeutics(APT) signed an agreement with the Israeli phage bank. APT made an upfront payment and will pay royalties from net sales on any therapeutic composition comprising a licensed phage. This is one-way phage banks can be self-sustaining. Also, through grants. 

The biggest hurdle we have in actualizing a phage bank in Nigeria are:

1. Electricity we hope to solve using solar energy
2. Consumables for sequencing and ultrafiltration of the phages
3. Funds for clinical trials 

Cost-Effectiveness Analysis of Phages 

Australia has a robust phage therapy network. Over a period of 6 years Substantial savings are made with phage therapy, i.e., $122.8M for prosthetic joint infection (PJI) and $67M for sepsis (over 3 years). See link to the reports. 

The summarised figure of savings by introducing phage therapy as part of AMR sepsis clinical service using Australia as a case study Source (https://dl.phage.directory/WIMR01_AMRSepsis_WP_FINAL_26July2022.pdf)

Key summary of their finding for evaluating the cost of using phages against Antibiotics

• If all AMR sepsis patients in Australia (2,461 patients) were treated with bacteriophage therapy, the total savings over three years were expected to be $67.0 million, or $27,239 per patient.
•  If all AMR sepsis patients in NSW (782 patients) received bacteriophage therapy, the total savings over three years were expected to be $21.3 million.
• The total direct savings (healthcare-related savings) were $21.8 million, all of which were paid for by the government.
• The total indirect savings (non-healthcare savings) were $45.2 million, with patients paying the most (63%) followed by employers (20%) and the government (17%).
• The length of stay for patients with AMR sepsis is estimated to be reduced by an average of 7.6 days per patient.
•  Resolved bacteriophage infection is predicted to reduce average time off work by 13.2 months per patient, minimizing potential lost income for patients who were working prior to hospitalization.
• Over a three-year period, 31 patients with AMR sepsis would avoid long-term disability (defined as not returning to work within three years of discharge), resulting in less home care, disability support, and the requirement for a primary caregiver.

Summarised figure of savings by introducing phage therapy as part of prosthetic joint infections clinical service source (https://dl.phage.directory/WIMR01_PJI_WP_FINAL_26July2022.pdf)

The key findings for PJI are:

• If all patients across Australia with prosthetic knee and hip infections (2,573 patients) were treated with bacteriophage therapy, the total savings over 6 years were estimated to be $122.8 million in 2022 corresponding to an average saving of $47,736 per patient over 2 years 15.
• If all patients across NSW with prosthetic knee and hip infections (818 patients) were treated with bacteriophage therapy, the total savings over 6 years were estimated to be $38.8 million in 2022 corresponding to an average saving of $47,424 per patient over 2 years 
• The total direct savings (healthcare relating savings) were $71.3 million most of which was attributed to the government (63%) and private health insurers (33%). Savings were also partially attributed to patients and their families (4%).
• The total indirect savings (non-health care related savings) were $51.5 million most of which was attributed to patients and their families (67%), followed by the government (19%) and employers (14%).
• The highest saving per patients were reported for hip joints ($49,376) and patients with chronic infections ($45,131). Greater saving per patients were incurred in the first 4 years ($50,846 for year 0-2, $46,153 for year 2-4 and $25,207 for year 4-6).

Based on these health economics calculations, we may conclude that phage therapy is now an efficient use of public health funds.

In the context of Nigeria and Africa, establishing a phage bank can be beneficial in several ways:

1. Novel Treatment Options: Phages can target specific bacteria, even those that have developed resistance to antibiotics. By having a diverse collection of phages in a bank, healthcare providers can access a wider range of treatment options for bacterial infections.
2. Tailored Solutions: Phages can be isolated and characterized from local environments, allowing for the development of region-specific phage therapies. This can be particularly valuable in Nigeria and Africa, where specific bacterial strains and resistance patterns may differ from those found in other parts of the world.
3. Cost-effectiveness: Phage therapy has the potential to be more cost-effective than traditional antibiotic treatments. Developing a phage bank can help reduce the time and resources needed to isolate and prepare phages for treatment, making it a more accessible and affordable option, especially in resource-limited settings.
4. Preservation of Phage Diversity: Establishing a phage bank allows for the long-term preservation of phages with unique properties. It helps to safeguard these resources, ensuring their availability for future research and therapeutic purposes.
5. Research and Development: Phage banks can also facilitate research and development efforts, including the identification and characterization of new phages, understanding phage-bacteria interactions, and improving phage therapy protocols. This knowledge can contribute to the advancement of AMR strategies in Nigeria, Africa, and beyond.
6. Reduced reliance on antibiotics: By promoting the use of phage therapy, a phage bank could help reduce the reliance on antibiotics, thereby mitigating the development and spread of antimicrobial resistance.
7. Local production and accessibility: Establishing a phage bank in Nigeria or Africa could support local production and distribution of phages, making them more accessible to healthcare providers and patients in the region. This could potentially improve treatment options, particularly in remote areas with limited access to antibiotics.

Conclusion

In summary, establishing a phage bank in Nigeria and Africa could potentially contribute to the fight against antimicrobial resistance by providing access to diverse phages for tailored and cost-effective treatments. It can foster research and development efforts, supporting the region's efforts to combat AMR. I will be glad to discuss more on this.