The Promising Potential of Reverse Vaccinology-Based Next-Generation Vaccine Development over Conventional Vaccines against Antibiotic-Resistant Bacteria

Abstract

The clinical use of antibiotics has led to the emergence of multidrug-resistant (MDR) bacteria, leading to the current antibiotic resistance crisis. To address this issue, next-generation vaccines are being developed to prevent antimicrobial resistance caused by MDR bacteria. Traditional vaccine platforms, such as inactivated vaccines (IVs) and live attenuated vaccines (LAVs), were effective in preventing bacterial infections. However, they have shown reduced efficacy against emerging antibiotic-resistant bacteria, including MDR M. tuberculosis. Additionally, the large-scale production of LAVs and IVs requires the growth of live pathogenic microorganisms. A more promising approach for the accelerated development of vaccines against antibiotic-resistant bacteria involves the use of in silico immunoinformatics techniques and reverse vaccinology. The bioinformatics approach can identify highly conserved antigenic targets capable of providing broader protection against emerging drug-resistant bacteria. Multi-epitope vaccines, such as recombinant protein-, DNA-, or mRNA-based vaccines, which incorporate several antigenic targets, offer the potential for accelerated development timelines. This review evaluates the potential of next-generation vaccine development based on the reverse vaccinology approach and highlights the development of safe and immunogenic vaccines through relevant examples from successful preclinical and clinical studies.

Keywords: MDR bacteria; antibiotics; immunoinformatics; reverse vaccinology; vaccine.

Figure 1

Mechanisms of antibiotic resistance acquired through horizontal gene transfer such as (A) transformation, (B) transduction, and (C) conjugation.

Figure 2

Elicitation of humoral and cellular immune responses from the administration of next-generation vaccine platforms such as DNA-, mRNA-, and recombinant protein vaccines. The administration of DNA vaccines requires DNA to be taken up by antigen-presenting cells (APCs) such as dendritic cells. Once inside the cell, the DNA needs to reach the nucleus to be transcribed into messenger RNA (mRNA). After transcription, the newly synthesized mRNA is transported out of the nucleus into the cytoplasm. In the cytoplasm, the mRNA serves as a template for protein synthesis. mRNA vaccines, on the other hand, can be directly translated in the cytoplasm. Once the protein is synthesized in the cytoplasm, it can undergo further modifications and processing to acquire its final functional form. These proteins can then be presented on the surface of APCs, initiating an immune response and triggering the production of specific immune cells and antibodies that provide protection against the targeted pathogen. Recombinant protein vaccines may serve as antigens after processing by APCs and subsequently presented on MHC class I and class II molecules for the activation of CD4⁺ and CD8⁺ T cells. Specialized CD4⁺ T cells, namely T follicular helper (Tfh) and Foxp3⁺ T follicular regulatory (Tfr) cells, play crucial roles in facilitating germinal center B cell formation through interactions with T and B cells. Tfh cells provide assistance to B cells through interactions between CD40L on Tfh cells and CD40 on B cells, leading to the release of cytokines such as IL-2, IL-4, IL-21, and IFN-γ. These cytokines further stimulate the formation of germinal centers, promoting maturation into plasma cells that produce memory B cells and long-lived antibody-secreting plasma cells. On the other hand, CD8⁺ T cells directly combat infections by targeting and eliminating infected cells using perforin and granzymes, thereby restricting the pathogen’s spread within the body.