tl;dr: 

I  attended the last Blue Dot Pandemic Preparedness Course.  I outline my career development plan, such as seeking the capacity to design a phage-based Salmonella typhi vaccine  as a way to  seek further training and positioning myself for the next pandemic

What did the course do for me?

The course is 12 weeks long, consisting of 8 weeks of taught content and 4 weeks to work on a project where you start to take your next steps towards contributing to pandemic prevention. It is completely virtual and was my first detailed exposure to global catastrophic risk. 

My background is in medical microbiology, and I have a bias toward the use of phages in treating and managing drug resistance.  before attending the course, I had very faint knowledge of global catastrophic risk 

It was during the course, that I heard for the first time about the theory of change and how it impacts research formulation. I also learned about the role vaccines play in both preventing and mitigating pandemics.  My first verdict is that the course serves as a good primer for anyone interested in learning more about pandemic preparedness.  

Phage vaccine skill development: My next career-building activity. 

Vaccines represent an effective approach to preparedness against pandemics and other infections. The COVID-19 pandemic exposed a wide disparity in vaccine distribution. Only 26% received a single dose of COVID-19 vaccine in Low- and Low-Middle-income countries (LICs and LMICs), as opposed to over 80% in high-income countries (HICs). Consequently, in future pandemics, LICs and LMICs would be at higher risk due to potential delays, spanning months to years, in gaining access to first-generation vaccines that effectively target prevailing strains. This risk underscores the importance of addressing inherent limitations for global health equity. Therefore, there is a critical demand to develop intracontinental preparedness capacity against pathogens with a high potential to cause epidemics in Africa rather than depending solely on external sources. Generally, vaccines have demonstrated constraints, such as elevated expenses and suboptimal immune responses. In that regard, bacteriophages (phages) have been used in phage-display technology that produces vaccines by presenting the targeted antigen on the phage surface. This technology capitalizes on the intrinsic attributes of phages, including their adjuvant potential, cost-effective production, and high stability.

Phage-based vaccines, with their adaptable platform, promise substantial benefits: a swift response to diverse bacterial infections with pandemic potential; a self-adjuvant nature that enhances immune responses; an ability to display multiple antigens; genetic plasticity and stability; and cost-effectiveness for mass production. Moreover, their safe, well-understood therapeutic use in humans renders them ideal for resource-limited settings. I plan to seek further capacity to learn more about how to develop a phage vaccine. To do this, I plan to develop a phage vaccine for Salmonella typhi. This is aimed at designing and evaluating A Phage-based typhoid vaccine, that will provide an adjuvant-free, low-temperature dependent and needle-free alternative for typhoid fever that can be suitable for use in rural communities

Why Salmonella typhi Phage-based vaccine?

Typhoid fever infections pose significant public health challenges, particularly among children in low and middle-income regions such as Africa, Southeast Asia (including India, Pakistan, and Bangladesh), East Asia, and South America. Although antibiotic therapy has proven effective in reducing the clinical progression of enteric fever and lowering the risk of death, the rapid emergence of multidrug-resistant (MDR) strains of S. Typhi has substantially impacted the efficacy of antibiotic treatments, raising considerable public health concerns.

To address this issue, the World Health Organization (WHO) has recommended two licensed vaccines, namely Vi capsular polysaccharide (ViCPS) and the live attenuated oral Ty21a, since 2008 for the control of typhoid. These vaccines have demonstrated safety and cost-effectiveness in various countries (Cook et al., 2008). However, the Vi polysaccharide-based vaccine is ineffective against S. Typhi strains lacking Vi polysaccharide, and the Ty21a vaccine requires three doses with 10⁹ bacteria for sufficient immunity. Additionally, their moderate protection (50–70%) makes them unsuitable for infants under 2 years of age.

Recently, WHO introduced the Vi-TT conjugate vaccine as a pre-qualified vaccine against typhoid fever, specifically intended for use in India. The newer generation of typhoid conjugate vaccines is expected to offer higher efficacy, longer duration of protection, and suitability for administration to infants and young children. Notably, the carrier proteins in these conjugate vaccines do not originate from the salmonella proteome, and limited clinical experiments are available to validate these assumptions.

Despite numerous research efforts aimed at identifying potential vaccine candidates (VCs) that could confer long-term immunity and robust protection against Salmonella Typhi, no promising VCs for typhoid fever infection have emerged from large-scale clinical trials. Consequently, ongoing endeavours focus on the continuous identification of additional vaccine antigens capable of eliciting optimal immune responses against typhoid fever infections and antibiotic-resistant isolates.

Theory of Change:

The overall impact of the career-building activity is to develop a phage-based vaccine against Salmonella typhi that will lead to improved well-being and a reduction in morbidity and mortality associated with typhoid fever.  The rationale for this is that phages require less equipment to manipulate and have been used as potent vaccine platforms. Salmonella presents a low-hanging fruit to test the practicability of adopting this technology for use in Africa, although the pathogen does not have pandemic potential, it is endemic in Sub-Saharan Africa. Developing a vaccine such as this will go a long way in increasing our capacity/skill to design or formulate a vaccine against pathogen X in the face of any outbreak. It will also bring about a vibrant and active phage research laboratory in Nigeria that would have the requisite skills to manipulate phages for endemic and pandemic pathogens.   The project aims to design a phage-based vaccine that has a broad capacity to protect against major Salmonella pathogens, has a high immunogenicity, and does not require an adjuvant or needle for administration. To achieve this, the project intends to apply the reverse technology 2.0 approach to identifying potential epitopes/targets for vaccine design and incorporate these targets into the phages. Evaluate them using mice under different administration processes such as drying the phages in powder to increase their longevity and administering them using water.

Rough BOTEC  on The potential of the effectiveness of a Salmonella phage-based vaccine

Probability for success

I will put this at 40%. Phage vaccine prototypes were developed during the COVID-19 pandemic (links to paper 1, paper 2). Phage technology is recently been developed in Africa. My lab is pioneering this. I registered a charity dedicated to phage research, the lab is open to researchers across Africa. It hopes to serve as a phage bank.  

Plan A: If I get funding to visit a lab

I am seeking support for the opportunity to learn and develop this very important skill. So. The first plan is to seek funding. If I get funded, I hope to take a sabbatical leave to learn this.  I will be glad to talk with you and hear more about possible funding sources for this career activity.

Plan B: If I do not get funded to visit a lab

This is a tricky one, but I am committed to learning. When I first heard about phages, I applied to visit several labs to learn phage techniques, but no one gave me the opportunity. So I decided to go to the lab and learn it myself. I went on to become the first lab to report a phage genome in Nigeria, and in the 2 years since coming into phage research, I have emerged as one of the leading phage researchers in Nigeria and Africa. I currently co-lead the African Phage Forum. 

So, in the event, I do not get funded to visit a lab, I shall seek funding to self-train myself in my lab. 

Conclusion

My next career step in building the capacity to position myself in Nigeria for the next pandemic is to seek the capacity to learn how to design phage vaccines. I plan to use Salmonella typhi as a test pathogen.  I hope I go ahead to become successful with getting support and funding.  I will be glad to hear about opportunities, partnerships, or getting a sponsorship. Above all, I would like to hear what you think about this project idea.  If you like to chat, feel free to reach out to me via eennadi@gmail.com

References

Chen, J., ., 2023, May. Taking on Typhoid: Eliminating Typhoid Fever as a Global Health Problem. In Open Forum Infectious Diseases (Vol. 10, No. Supplement_1, pp. S74-S81). US: Oxford University Press.

Cook J, Jeuland M, Whittington D, Poulos C, Clemens J, Sur D, et al. The cost-effectiveness of typhoid Vi vaccination programs: calculations for four urban sites in four Asian countries. Vaccine. 2008;26(50):6305-16.

Kim, J.H. et al.,, 2023. Occurrence of human infection with Salmonella Typhi in sub-Saharan Africa. medRxiv, pp.2023-09

Phillips, M.T. et al., 2023. Cost-effectiveness analysis of typhoid conjugate vaccines in an outbreak setting: a modeling study. BMC infectious diseases, 23(1), pp.1-15.