Vaccination as a tool to decrease antimicrobial resistance

Since the introduction of penicillin, bacteria have gradually developed mechanisms to resist its effects. To date, hundreds of antibacterial agents have been developed, and bacteria have evolved various mechanisms of antimicrobial resistance (AMR). Some of the key mechanisms include:

1. Reduced Permeability: Mutations in bacterial porins decrease the entry of the antibacterial agent. A well-known example includes penicillin-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (Shown as Mechanism 1, in Figure-1).
2. Efflux Pumps: Once the antibacterial agent enters the bacterial cell, efflux pumps can be activated to expel the drug. This is a common mechanism, particularly in Enterobacteriaceae against aminoglycosides, though not exclusive to them. (Shown as Mechanism 2, in Figure-1).
3. Receptor Modification: Bacteria can alter the receptors on their ribosomes, thereby reducing the binding effectiveness of protein synthesis inhibitors, such as aminoglycosides, tetracyclines, and macrolides. (Shown as Mechanism 3, in Figure-1).
4. Enzymatic Inactivation: Perhaps the most widespread mechanism, enzymatic inactivation involves the production of enzymes like beta-lactamases, which break down drugs such as beta-lactam antibiotics. (Shown as Mechanism 4, in Figure-1).

Figure-1: Mechanisms of AMR:

AMR can be rapidly transmitted between bacteria through horizontal gene transfer, primarily via conjugation (bacteriophages). This efficient spread has led to the rapid global dissemination of resistant strains, making antimicrobial resistance a major health threat. In 2019 alone, AMR was responsible for an estimated 4.9 million deaths worldwide.

The use of antimicrobial agents in animals is the largest contributor to global antimicrobial consumption. In 2019, the World Organization for Animal Health (WOAH) estimated that 84,500 tons of antimicrobials were used in the animal sector, although this represented a 13% decrease compared to 2017. In contrast, global antibiotic consumption in humans increased by 65% between 2000 and 2015, with the most significant rise occurring in low- and middle-income countries (LMICs). This trend is expected to triple by 2030, compared to 2015 levels, unless effective interventions are implemented. A major challenge is ensuring equitable access to antimicrobials, particularly in LMICs, where the lack of access to effective treatments may pose a greater risk to public health than antimicrobial resistance itself.

Indeed, regulating and restricting the use of antibacterials are crucial measures to prevent the spread of AMR. However, as illustrated in the figure below (Figure 2), several other interventions can complement these efforts. These include the development of better, faster, and cost-effective diagnostic tools to accurately distinguish viral infections and avoid unnecessary antibacterial prescriptions; strategies to maintain microbiota balance (the best example is how gut microbiota influences the growth of Clostridium difficile); the use of more selective antibacterials; the development of monoclonal antibodies; bacteriophages engineered with counteracting genetic information against AMR; and the use of vaccines.

Figure-2: Interventions to prevent AMR (Reproduced with permission of Micoli F, Bagnoli F, Rappuoli R, Nature Rev 2021; 19: 287-302).

Now, how can vaccination help prevent the dissemination of AMR?

As illustrated in Figure 3, from an individual perspective, an unvaccinated person with a bacterial infection would typically require one or more antibiotics, so called first – and second – line antibacterials. Now, in a population with many unvaccinated individuals, increased prescription of antibiotics would lead to the rapid spread of both bacterial infections and AMR in the community, with a range of negative consequences.

However, when individuals are vaccinated, both on a personal and population level, vaccination helps prevent infection. As a result, the need for first- or second – line antibiotics becomes rare, as shown in Figure 4.

Figure 3. AMR transmission without vaccination (Reproduced with permission of Micoli F, Bagnoli F, Rappuoli R, Nature Rev 2021; 19: 287-302).

Figure 4. AMR prevention thru vaccination (Reproduced with permission of Micoli F, Bagnoli F, Rappuoli R, Nature Rev 2021; 19: 287-302).

Pneumococcal vaccination, particularly with the current pneumococcal polysaccharide-protein conjugate vaccines (PCVs), provides a clear example of how vaccination can reduce antibiotic prescriptions and, consequently, decrease pneumococcal AMR. This effect is observed both in terms of nasopharyngeal colonization and in cases of disease, with a reduction of up to 62%, especially against penicillins, cephalosporins, and macrolides.

In addition, the meningococcal B vaccine is estimated to provide 33–47% protection against gonorrhea, potentially helping to reduce AMR associated with this widely spread pathogen.

On the other hand, viral infections often result in the inappropriate overprescription of antibiotics, which contributes to the spread of antimicrobial resistance (AMR). Accordingly, vaccination against both influenza and SARS-CoV-2 has been shown to reduce the need for antibacterial prescriptions, thereby helping to mitigate the rise of AMR.

In 2024, the World Health Organization has published a report entitled “Estimating the impact of vaccines in reducing antimicrobial resistance and antibiotic use”. 

Globally, vaccines and vaccination could annually avert up to 408 000 deaths, 23.0 million DALYs, US$ 30.0 billion in hospital costs and US$ 17.7 billion in productivity losses, all associated with AMR. 

The report evaluates the impact of both already licensed vaccines and those currently in development.

Each year, vaccines against the following diseases could significantly reduce antibiotic use:

• Streptococcus pneumoniae: Vaccinating 90% of the world’s children, as targeted by the Immunization Agenda 2030, along with older adults, could save up to 33 million antibiotic doses.
• Typhoid: Accelerating the introduction of typhoid vaccines in high-burden countries could save 45 million antibiotic doses.
• Malaria (Plasmodium falciparum): The malaria vaccine could prevent up to 25 million antibiotic doses, which are often misused in attempts to treat malaria.
• Tuberculosis (TB): Once developed, TB vaccines could have the greatest impact, saving between 1.2 and 1.9 billion antibiotic doses — a significant portion of the 11.3 billion doses used annually to treat the diseases covered in this report.

The WHO report also assesses the role of vaccines in mitigating AMR and provides actionable recommendations for key stakeholders on how to enhance vaccines’ effectiveness in addressing AMR. The analysis covers 44 vaccines targeting 24 pathogens, including 19 bacterial species, four viruses, and one parasite. Given that infections can cause multiple syndromes and impact different age groups, several vaccines targeting the same pathogen were evaluated for their potential to reduce AMR.

The pathogens examined in the report include: Acinetobacter baumannii, Campylobacter jejuni, Clostridioides difficile, Enterococcus faecium, Enterotoxigenic Escherichia coli (ETEC), Extraintestinal Pathogenic Escherichia coli (ExPEC), Group A Streptococcus (GAS), Haemophilus influenzae type B (Hib), Helicobacter pylori, Klebsiella pneumoniae, Mycobacterium tuberculosis, Neisseria gonorrhoeae, nontyphoidal Salmonella, Pseudomonas aeruginosa, Salmonella paratyphi A, Salmonella typhi, Shigella, Staphylococcus aureus, Streptococcus pneumoniae, Plasmodium falciparum (malaria), influenza, norovirus, rotavirus, and respiratory syncytial virus (RSV).

Indeed, vaccines offer numerous opportunities to prevent diseases, reduce hospitalizations, save lives, and lower healthcare costs. By helping to reduce AMR, vaccines play an additional critical role in improving global health, making them essential for human well-being and long-term survival.

Bibliography:

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