Will the mRNA vaccine platform be the panacea for the development of vaccines against antimicrobial resistant (AMR) pathogens?

KEYWORDS:

• Antimicrobial Resistance (AMR)
• mRNA vaccine
• vaccine
• alternatives to antibiotics
• bacterial infection

1. Antimicrobial resistance

Antimicrobial resistance (AMR) has emerged as a major global public health catastrophe [1]. Annual global deaths from AMR pathogen infections have been estimated to be ~700,000 and could reach 10 million by 2050, exceeding those due to cancer [2]. In addition, AMR could result in up to 24 million people into extreme poverty by 2030 if no action is taken [3]. The COVID-19 pandemic further exacerbates the AMR crisis because of the increased use of antibiotics for secondary bacterial infections and the delayed global action against AMR [4]. As such, AMR has been recognized as a ‘silent’ or ‘the next’ pandemic by medical professions and public health experts [5].

New and distinct classes of antimicrobials are urgently needed to develop for patients infected with AMR pathogens. Unfortunately, there have been few recent successes in developing new antibiotics with improved potency and safety. More importantly, these new antibiotics will also be subject to the same selective pressures responsible for the emergence of current AMR pathogens. To avoid resistance development, substantial efforts have been invested in developing alternatives to antimicrobials, such as bacteriophages, nanodelivery systems, antibodies, vaccines, probiotics, microbiota, and CRISPR, etc. [6]. Among them, vaccines are one of the most attractive and cost-effective strategies against infections without the induction of drug resistance [7]. However, the development of vaccines against AMR pathogens (AMR vaccines) has encountered scientific and logistic challenges due to the opportunistic nature of many AMR infections, overall low incidence of AMR cases, and the often immunocompromised hosts (e.g. elderly, hospitalized). This, coupled with the lengthy (usually 10–20 years) and expensive discovery-to-market process of vaccine development, has limited the financial incentive for vaccine industries to pursue such a strategy [8]. Therefore, no licensed vaccines are currently available for most of the AMR pathogens of high priority. A few that have advanced into clinical trials (such as vaccines for Clostridium difficile, Pseudomonas. aeruginosa, and Staphylococcus aureus) have generally shown disappointing results [7]. Thus, innovative approaches are needed for the development of vaccines as an alternative to combat AMR.

2. COVID-19 responses and the rising of mRNA vaccine platform

The great success of the mRNA vaccine platform to develop SARS-CoV-2 vaccines in less than one year, from sequencing of the virus to Emergency Use Authorization approval, has generated unprecedented enthusiasm on its potential in the development of vaccines against other infections and non-communicable diseases. Like DNA vaccines, mRNA vaccines introduce genetic instructions (mRNA encoding disease/pathogen-specific antigen) into host cells (cytosols) to produce the protein antigen in situ. This antigen is then displayed on the cell surface to activate host innate immunity and induce specific T cell and antibody responses. In the case of many COVID-19 mRNA vaccines, modified or unmodified genetic code of the full-length spike protein is delivered and translated into S protein [9]. To develop an AMR vaccine, theoretically, all we needed is the mRNA sequence of the antigen from the AMR pathogen of interest, which allows us to design and test the vaccine constructs within weeks.

The clinical trial results of Pfizer-BioNTech and Moderna SARS-CoV-2 mRNA vaccines have shown that both vaccines provide comparable or superior protection against diseases, transmission, and variants of concern to other traditional vaccine platforms (such as inactivated, subunit, and viral vectored vaccines) [10,11], These studies have also demonstrated that mRNA vaccines are generally well-tolerated by healthy individuals with a few side effects. Compared with viral vector platforms, mRNA vaccines are unlikely to develop anti-vector immunity and are safer for immunocompromised populations. Due to these advantages, there is currently a renaissance in the development of mRNA vaccines for influenza, Ebola, Zika, malaria, and cancers.

3. The potential of mRNA vaccines against AMR pathogens

There are several competitive advantages to applying the mRNA vaccine platform in the development of AMR vaccines. The rapid vaccine design and potential ‘plug and play’ module of the platform will significantly reduce the R&D cost [12] and, therefore, make the development of AMR vaccines for a small targeted population financially attractive. Since AMR pathogens include many species and strains, the development of multicomponent vaccines in this platform is feasible by either encoding multiple antigens in a single vaccine construct or mixing multiple mRNA vaccines in a single immunization (such as Modern mRNA-1273.211 vaccine) [13]. As demonstrated in the COVID-19 pandemic, mRNA vaccines can be produced more rapidly in a process that can be easily standardized. With the accumulation of large amounts of preclinical and clinical data on the immunogenicity, efficacy, and safety of this platform, expedited regulatory approval of mRNA vaccines in the future is possible. This will have a major impact on AMR vaccines since AMR pathogens are emerging and reemerging rapidly and unpredictably.

Current efforts on mRNA vaccine development have focused on viral infections and cancer although encouraging preclinical results have been recently reported in the malaria vaccine [14]. Additional studies will be needed to determine the potential of this platform for AMR vaccines since most AMR pathogens of interest are bacteria and fungi. In this regard, at least two laboratories have performed some pioneering work on mRNA vaccines against bacterial infections. In 2004, Xue et al. have explored the potential of mRNA vaccine against Mycobacterium tuberculosis and found that RNA constructs expressing the M. tuberculosis MPT83 antigen-induced specific humoral and T cell immune responses and conferred modest but significant short-term protection against M. tuberculosis H37Rv challenge in mice [15]. The lung bacterial burden in the immunized mice at 4 weeks after the challenge was about one log lower than in mice vaccinated with the control RNA vaccine but was about 10 folders higher than the mice vaccinated with BCG. However, it is noteworthy that the mRNA platform was less well advanced in 2004 than now. In this regard, more than 400 million doses of mRNA vaccines have been administrated globally as of November 6th, 2021 (https://ourworldindata.org/covid-vaccinations, accessed on 11 November 2021).

More recently, Maruggi et al. investigated the immunogenicity and efficacy of self-amplifying mRNA (sa-mRNA) vaccines against Group A (GAS) and Group B (GBS) Streptococci. Immunization with sa-mRNA vaccines encoding the double-mutated GAS Streptolysin-O or the GBS pilus 2a backbone protein (BP-2a) induced significant amounts of functional serum antibodies (opsonophagocytic killing and sheep blood cell hemolysis inhibition) and protected mice against lethal bacterial challenges [16]. Although the antibody responses and protection induced by sa-mRNA vaccines were weaker than those induced by recombinant proteins formulated with MF-59 or alum, these could be further enhanced by including a eukaryotic secretion signal peptide (the murine J chain leader sequence) to the N-terminus of BP-2a construct or by boosting with one dose of protein immunization [16]. The sa-mRNA vaccine also induced antigen-specific IgG2a (Th1) responses. These results demonstrate the potential of mRNA vaccines against AMR pathogens.

4. Potential challenges of development of mRNA vaccines against AMR pathogens

Despite the success of the mRNA vaccine platform in SARS-CoV-2 vaccines and its proof of concept in other vaccine candidates, its potential for AMR vaccine development remains to be determined. Before COVID-19, several viral and cancer mRNA vaccine candidates have been evaluated clinically without success. Even with SARS-CoV-2 vaccines, whereas Pfizer/BioNTech and Moderna vaccines had extreme success, the CureVac candidate showed disappointing results (~48% protection) [17]. Since all three vaccines target the spike protein, crucial differences in their design, doses and delivery may contribute to the different efficacies. In this regard, the dose used in the CureVac vaccine contains only 12 µg mRNA (relative to 30 or 100 µg for the other two licensed mRNA vaccines) and uses unmodified RNA Thus, further fundamental research is needed to understand the critical parameters that determine mRNA vaccine efficacy. In this regard, strategies to optimize mRNA sequences to increase their stability and translational efficiency and minimize unintended host innate immune responses to foreign mRNA have been introduced [9]. Moreover, targeted delivery of mRNA to antigen-presenting cells and specific (lymph) tissues should improve the immunogenicity and safety of mRNA vaccines [17]. Furthermore, active research is ongoing to reliably produce mRNA vaccines that can be stored outside the cold chain.

There are also certain specific challenges in the successful application of the mRNA vaccine platform to develop AMR vaccines. For example, the platform is limited to express protein antigens, whereas many AMR pathogens are Gram-negative bacteria and the protective immunity is often directed against the surface polysaccharide capsules. In addition, like with other vaccines, bacteria can simply switch to alternative resistance mechanisms to evade what would be very clonally defined antibody pressure. Finally, the target population of AMR vaccination is largely aged and immunocompromised, which demands robust immunogenicity and excellent safety of the vaccine. As such, the cost and time involved in safety and efficacy trials and licensing of AMR vaccines, including mRNA vaccines, remain a considerable challenge.

5. Conclusion

The increased threat of emerging AMR to public health and societal prosperity demands the availability of new antibiotics and alternatives to antimicrobials. Vaccination is a highly cost-effective medical invention against infectious diseases with minimal risk to induce drug resistance. However, the progress in the development of AMR vaccines has been slow partly due to issues associated with multiple pathogens involved, the small target population for vaccination, the difficulty to conduct clinical trials, and the financial viability. The recent success of mRNA vaccine technology in the rapid deployment of SARS-CoV-2 vaccines has shown several advantages of this technology that are attractive for the development of AMR vaccines. These include its speed to design and produce, high protection efficacy and good safety profiles, and potentially low R&D cost and fast regulatory approval. With many mRNA vaccines and therapeutics currently under active development, we anticipate that some challenges to this platform will be solved and novel strategies, such as alternative mRNA vaccine platforms (self-amplifying or trans-amplifying RNA) [18], developed in the next few years. Thus, the mRNA vaccine platform could be a promising solution to the challenges currently encountered in AMR vaccine development although the jury is still out on the eventual application of mRNA-based AMR vaccines.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

W. Chen: Conceptualization, Investigation, Writing - review & editing.

Additional information

Funding

The antimicrobial resistance research in our laboratories has been supported by NRC intramural (A-base) program under the Vaccine and Emerging Infection Research Initiative (Human Health and Therapeutics) and NRC Ideation Small Team Project (National Program Office). The view expressed here is solely the responsibility of the author and does not necessarily represent the official views of NRC.