Beyond antibiotics: Vaccines as catalysts for one health solutions to antimicrobial resistance

INTRODUCTION

Antimicrobials are drugs used to treat infections in animals or humans by either killing or inhibiting the growth of microorganisms causing the infection. They consist of agents such as antibiotics, antifungals, antivirals, and anthelmintics.^[1] Antimicrobial resistance (AMR) has recently emerged as a global health issue. AMR occurs when viruses, bacteria, fungi, and parasites do not respond to antimicrobial treatments in animals or humans, thereby allowing the survival of the microbe within the host.^[2] AMR has been prioritized by the World Health Organization (WHO) as one of the top ten global public health threats humanity grapples with. The issue has attracted notable political will from the G7 countries, continuing to be on the agenda of several meetings.^[3] The High-Level Meeting of the United Nations General Assembly on AMR in 2016 officially declared the importance of AMR, soliciting nations to commit to their individual AMR action plans. In spite of these efforts, drug-resistant infections contributed to an alarming 4.95 million deaths worldwide in 2019, with the larger proportion of the clinical burden borne by low- and middle-income countries (LMICs) which outweighs the annual global deaths due to tuberculosis (TB) (1.5 million), human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (864,000), and malaria (643,000). Left unattended, estimates project that global deaths due to AMR could reach 10 million per year by 2050.^[2,4] AMR causes are multifaceted, but clearly, antimicrobial overuse has been paramount.^[2] Indeed, the main cause of the current crisis remains to be the improper use of antimicrobials, particularly the inappropriate usage of antibiotics, increasing the global burden of AMR. The importance of public health promotion still needs to be further emphasized as part of action plans.^[3] Antimicrobial misuse includes the increased prescription of antibiotics by doctors for viral infections such as influenza or the common cold, against which these drugs are ineffective, promoting the development of resistant bacteria. Prescribing broad-spectrum antibiotics annihilates normal flora along with the pathogenic ones. Patients sometimes discontinue antibiotics as soon as they feel better, rather than completing the prescribed course, leaving surviving bacteria that may develop resistance but may also misuse antibiotics by self-prescribing leftovers from previous prescriptions or obtaining them without a prescription, contributing to resistance. In agriculture where antimicrobials are usually used in livestock to promote growth and prevent disease, even in healthy animals, this causes the emergence of resistant bacteria that can be transmitted to humans.^[5] As shown by the high levels of antimicrobial residues found in meat for consumption, livestock represents a major source of resistant pathogens, which are more likely to be transmitted to humans.^[1] Vaccines have proved to be important in limiting the spread of resistant pathogens, and the consequent AMR represents a major immunological milestone as their utility in the prophylaxis worldwide prolongs life expectancy.^[5] In contrast, the likelihood of developing resistance mechanisms to vaccines is extremely low, even in the rare instances in which resistance to vaccines has been reported; a reduction in disease burden has been achieved anyway.^[6] The aim of this review is to position vaccines as central One Health solutions to AMR.

ASSESSMENT OF PUBLICATIONS ON AMR

The review synthesized interdisciplinary data spanning human, animal, and environmental sectors, prioritizing how vaccines lower antimicrobial use, limit pathogen transmission, and contribute to lasting AMR control. Relevant literature was retrieved from sources such as PubMed, Scopus, Web of Science, and Google Scholar. Search terms included combinations of “vaccines,” antimicrobial resistance,” “One Health,” “antimicrobial stewardship,” “zoonoses,” “veterinary vaccines,” “environmental AMR,” and preventive vaccination.” Gray literature, including the WHO, Food and Agriculture Organization, World Organization for Animal Health (WOAH), and United Nations Environment Programme policy briefs, was also reviewed to capture current global frameworks and initiatives.

The inclusion criteria encompassed peer-reviewed articles published between 2000 and 2025, written in English, and addressing vaccines in relation to AMR or One Health integration. Studies were considered if they covered human, animal, or environmental domains relevant to AMR, incorporated policy briefs or gray literature from global health bodies, and presented biological mechanisms, epidemiological outcomes, or vaccinebased interventions against AMR. Exclusion criteria ruled out articles not available in English, studies published before 2000 or lacking relevance to AMR or vaccines, literature focused solely on antibiotic pharmacology without reference to resistance or prevention, reports without cross-sectoral implications, and editorials or commentaries without empirical data or policy relevance. Reference lists of key articles were manually screened to identify additional sources.

Extracted data emphasized mechanisms by which vaccines influence AMR, including their role in reducing antimicrobial consumption, limiting pathogen transmission, and strengthening population immunity. The review also captured evidence on cross-sectoral integration within the One Health framework, highlighting innovations and policy frameworks that support vaccine-based AMR control, as well as barriers and opportunities for implementation in LMICs. A thematic synthesis was applied to consolidate findings from biological, epidemiological, and policy perspectives. Evidence was organized within the One Health conceptual framework, depicting how vaccines function as ecological and behavioral interventions across interconnected systems, thereby reinforcing their role in sustainable AMR mitigation strategies.

LIMITATIONS OF CONVENTIONAL ANTIBIOTICS

Pathogens have evolved how to inactivate several classes of antibiotics. Among these, beta-lactam antibiotics (β-lactams), aminoglycosides (AGs), and chloramphenicol [Figure 1]^[5] are inhibited through the use of three main key enzymes: β-lactamases, aminoglycoside-modifying enzymes (AMEs), and chloramphenicol acetyltransferases (CATs), respectively [Figure 2], which broadly can be classified as antibiotic inactivation.^[7]

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Figure 1:

(a) A β-lactam antibiotic, (b) an aminoglycoside, and (c) chloramphenicol.

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Figure 2:

(a) Beta-lactam antibiotics of Vibrio parahaemolyticus, (b) aminoglycoside-modifying enzyme aminoglycoside phosphotransferase (2)-IVa of Enterococcus casseliflavus, and (c) type III chloramphenicol acetyltransferase of Escherichia coli.

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β-lactamases hydrolyze nearly all β-lactams that have amide or ester bonds, e.g., carbapenems, cephalosporins, monobactams, and penicillins.^[7] AGs are neutralized by specific enzymes: acyltransferases, phosphoryltransferases, and nucleotidyltransferases. These AMEs reduce the affinity of a modified molecule, occlude binding to the 30S ribosomal subunit, and provide extended-spectrum resistance to AGs and fluoroquinolone (FQ). AMEs are identified in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae strains.^[8,9] Few Gram-positive and Gram-negative bacteria and some of Haemophilus influenzae strains are resistant to chloramphenicol, and they have an enzyme CAT that acetylates hydroxyl groups of chloramphenicol; hence, this modified chloramphenicol is unable to bind to a ribosomal 50S subunit properly.^[10] AMR develops through several molecular mechanisms that enable pathogens to evade antimicrobial action. One major pathway is enzymatic inactivation, where bacteria produce enzymes such as β-lactamases, AG-modifying enzymes, or CATs that degrade or modify antibiotics.^[11] Another mechanism is target modification, including altered penicillinbinding proteins (PBP) (e.g., PBP2a in S. aureus), methylation of ribosomal ribonucleic acid (RNA) reducing macrolide binding, and mutations in gyrA/parC conferring FQ resistance.^[12] Resistance can also arise from reduced uptake and permeability, particularly in Gram-negative bacteria that modify outer membrane porins to limit drug entry.^[13] Finally, efflux pumps actively expel antibiotics from the cell, lowering intracellular concentrations below therapeutic thresholds; families such as major facilitator superfamily and resistance nodulation division transporters contribute to multi-drug-resistance (MDR) across several antibiotic classes.^[14] The global health impact of these mechanisms is profound. AMR was directly responsible for 1.27 million deaths and associated with 4.95 million deaths worldwide in 2019.^[4] Projections estimate that AMR could cause up to 10 million deaths annually by 2050, with cumulative economic losses reaching USD 100 trillion.^[15] LMICs are disproportionately affected due to weak surveillance, limited vaccine coverage, and high rates of antimicrobial misuse. [Figure 3] provides a comprehensive schematic linking AMR mechanisms to clinical outcomes (treatment failure, prolonged hospitalization), populationlevel effects (MDR, prevalence, transmission), and macrolevel impacts (mortality, economic loss).^[4,15]

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Figure 3:

Pathways of antimicrobial resistance and consequences for clinical and global outcomes.

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Mutated DNA gyrase and topoisomerase IV lead to FQ resistance: Quinolones bind to DNA gyrase A subunit. The mechanism of resistance involves the modification of two enzymes: DNA gyrase (coded by genes gyr A and gyr B) and topoisomerase IV (coded by genes par C and par E). Mutations in genes gyr A and par C lead to the replication failure and as a result, FQ cannot bind.^[16] At the same speed, where these antimicrobials are entering the cell, efflux mechanisms are pumping them out again, before they reach their target. These pumps are present in the cytoplasmic membrane. Most antibiotics of all classes are susceptible to the activation of efflux systems. Most efflux pumps are multi-drug transporters that are capable to pump a wide range of unrelated antibiotics – FQ, macrolides, and tetracyclines and thereby significantly contribute to MDR.^[17,18] Alterations in target biomolecules can greatly affect molecular binding with antimicrobials. Such changes can involve targets such as the ribosomal 30S and 50S subunits but also cell wall precursors and enzymes with crucial roles in RNA transcription or DNA replication.^[5] AGs bind to the 30S ribosomal subunit, whereas chloramphenicol, lincosamides, macrolides, and streptogramin B bind to the 50S ribosomal subunit to suppress translation. Point mutations in the rpoB gene encoding the RNA polymerase β-subunit mediate resistance to rifampicin.^[18,19] Despite the great efforts made by researchers and companies to develop new antimicrobial drugs, only a few molecules have been recognized so far as effective antibiotic candidates. In fact, the number of new antimicrobials developed later than the 1990s has progressively diminished, and many of them correspond to slight modifications of existing drugs. The search for new antimicrobials is challenging, and this can be due to several factors, which are mainly classifiable as scientific and commercial difficulties.^[5] Therefore, research is constantly focused on the identification of novel compounds that may be effective in treating such microbes.^[5] [Table 1] provides a structured summary of resistance mechanisms across major antibiotic classes. It highlights enzymatic degradation, altered targets, reduced uptake, and efflux pumps, linking each to representative pathogens. This table anchors the mechanistic discussion by showing how diverse molecular strategies converge to drive MDR.^[7-10,17-23]

[Figure 4] illustrates the principal bacterial AMR strategies, categorized into four mechanisms: Reduced drug uptake, enhanced drug efflux, structural modification of drug targets (e.g., PBPs), and enzymatic inactivation of drug molecules (e.g., β-lactamases), highlighting their molecular basis and clinical relevance.^[20]

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Figure 4:

Diagrammatic overview of bacterial antimicrobial resistance mechanisms, grouped into four primary strategies: (i) restricting drug entry, (ii) enhancing drug efflux, (iii) altering the structure of drug targets, and (iv) chemically inactivating the drug.

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VACCINES IN HUMAN HEALTH AND AMR

Vaccines and antibiotics have different mechanisms of action, and this results in a much lower probability of developing resistance after vaccination. Since they are prophylactic agents, vaccines work efficiently before pathogens replicate and spread in different organs. This is crucial to minimize the likelihood of drug resistance caused by mutations in the pathogen genome.^[5] In marked contrast, the probability of developing resistance mechanisms to vaccines is extremely low, and even in the rare instances in which resistance to vaccines has been reported, a reduction in disease burden has been achieved anyway. This is an important difference with antibiotics, for which the effect on a patient can be completely abolished by the emergence of resistance. Vaccines are usually administered before bacteria start to multiply and protect the patient from possible infections. On the other hand, antibiotics act therapeutically on ongoing infectious diseases and encounter an increased number of bacteria with a high probability of selecting resistant variants. Differently from antibiotics that have a specific bacterial target, vaccines induce immune responses against multiple targets (called antigens) and/or multiple epitopes of the same antigen (polyclonal antibodies). Consequently, the risk of emergence of vaccine escape mutants is greatly decreased since several mutations would be required for different epitopes.^[6] As a case in point, the effect of vaccination against Streptococcus in the USA reduced by 84% the cases of S. pneumoniae caused by MDR in children younger than 2 years of age. Even in the rare case of resistance to vaccines, two of which involved vaccination against bacterial pathogens (S. pneumonia and Bordetella pertussis), a severe outcome of the disease is still avoided due to the preventive nature of vaccines. Such effects have been well documented with H. influenzae type b, Pneumococci, Meningococci, and Rotavirus vaccines.^[24] According to a clinical trial carried out in 2018 on 6–35-month-old children, individuals receiving quadrivalent influenza vaccines showed a 47% lower incidence of influenza compared to the placebo group. This outcome was accompanied by a 50% reduced antibiotic prescriptions.^[25] Similar results were obtained in Ontario, where the vaccination of children against influenza led to a 64% reduced antibiotic prescriptions with respect to other provinces in Canada.^[26] In addition, the duration of the protection and the herd immunity, if attained, make the vaccines more efficient and reliable tools than antibiotics.^[5] In marked contrast, the probability of developing resistance mechanisms to vaccines is extremely low and, even in the rare instances in which resistance to vaccines has been reported, a reduction in disease burden has been achieved anyway.^[6] [Table 2] illustrates the impact of vaccines on reducing AMR in human populations. It documents reductions in MDR S. pneumonia cases, alongside decreased antibiotic prescriptions following influenza vaccination. This evidence underscores vaccines as prophylactic tools that lower antibiotic demand and resistance emergence.^[24-26]

VETERINARY AND LIVESTOCK VACCINES

Veterinary vaccines have played a significant role in safeguarding both public and animal Health, lessening animal suffering, facilitating the efficient production of food animals to feed the growing human population, and significantly lowering the need for antibiotics to treat companion and food animals. Vaccines against rabies and rinderpest are notable examples.^[27] Studies have shown that immunizing Danish pig herds against L. intracellularis, the cause of ileitis, can cut the amount of oxytetracycline used to treat the illness by about 80%.^[28] Significant variations in antibiotic consumption were reported between vaccinated and control flocks in a multi-center field trial of an Avian colibacillosis vaccine in broiler chicken, with consumption estimates averaging 0.5 treatment days for vaccinated flocks and 2 days for unvaccinated flocks.^[29] For instance, a live-attenuated Salmonella vaccine was used in experiments on commercial chicken farms by Islam and Rahman et al. According to the study, the frequency of Salmonella in the reproductive tracts (14.22% vs. 51.7%; P < 0.001) and ceca (38.3% versus 64.2%; P < 0.001) was lower in vaccinated chickens than in non-vaccinated hens. According to research by Berghaus et al., the use of a killed Salmonella vaccine reduced the incidence of Salmonella infection in broiler chicken flocks by nearly 60%.^[30] Similarly, numerous studies demonstrated the efficacy of Poulvac^® (Zoetis, Parsippany, New Jersey, USA), an E. coli vaccine, against the avian pathogenic E. coli in poultry.^[31] Apart from the emergence of resistance among microorganisms, the existence of drug residue in animal wastes and processed animal products are further issue brought on by the overuse of antibiotics in food animals which raises food safety issues such as toxicity, sensitization, allergies, and carcinogenicity.^[30] Bacterial vaccines reduce antibiotics by preventing and lessening the impact of bacterial infections, thereby supporting AMR control. By stimulating the immune system, these vaccines provide long-term, pathogen-specific protection that decreases infection rates and disease severity, reducing the need for therapeutic antibiotics.^[31] Complicated infrastructure, continuous maintenance, and operating expenditures result in high costs. Vaccine production requires advanced scientific and technical expertise, reliable electricity, access to replacement parts, robust cold-chain systems, and skilled human resources.^[32]

COMPANION ANIMALS AND AQUACULTURE VACCINES

The majority of canine parvovirus (CPV) infections have been documented in young dogs, most likely as a result of stressful situations or a lack of particular and protective vaccinations.^[33] The CPV vaccinations now in use offer cross-protection against all three types and are both safe and efficacious. The best defense against viral illness is still their sensible usage in conjunction with proper cleanliness practices. In addition, as recently proposed, vaccination lessens the needless use of antibiotics.^[33] Similarly, compared to unvaccinated animals, vaccinated dogs and cats have much decreased likelihood of getting systemic or highest-priority critically necessary antibiotics, according to data from companion animal surveillance.^[34] Aquaculture vaccines have become essential replacements for antibiotic prophylaxis in fish farming by preventing and controlling infectious diseases caused by bacteria and viruses.^[35] Recent therapeutic options used to address illness issues in aquaculture include vaccines and medications based on nanotechnology. Interest in employing nanoparticles as medicine and vaccine delivery vehicles has increased due to their tiny size and ability to pass through biological barriers. Promising outcomes were shown by nano-based vaccinations against several dangerous fish diseases, such as the lymphocystis disease virus and Vibrio anguillarum. These nanoparticles act as a disease-prevention tactic by boosting the immune responses of farmed fish.^[36] Monovalent and multivalent vaccines exist. Moreover, live, inactivated, or genetically engineered vaccines are also available. The three most used vaccination techniques in aquaculture are injection, immersion, and oral immunization. Vaccines must be administered before pathogen contact to provide fish enough time to acquire immunity.^[36] [Table 3] extends the analysis to veterinary and aquaculture domains, detailing vaccine efficacy against pathogens such as Flavobacterium columnare, Aeromonas hydrophila, and Canine parvovirus. By reducing infection rates and antibiotic reliance in animals, these vaccines prevent resistant microbes and residues from entering food chains and ecosystems.^[36,37]

SOCIOECONOMIC AND STRUCTURAL APPROACHES

Despite these clear health and economic advantages of vaccines, formal cost-benefit analyses of vaccines targeting AMR reduction in animal production are very limited. According to WOAH, vaccines are a cost-effective tool for preventing diseases and reducing the use of antimicrobials in livestock, although this is supported by limited quantitative data.^[38] Vaccines are not only biomedical interventions but also cost-effective public health tools. The WHO reports that pneumococcal vaccination programs significantly reduce healthcare expenditure by lowering antibiotic prescriptions and hospitalizations.^[39] Despite global childhood vaccine coverage exceeding 85%, uptake in many LMICs remains below 60%, reflecting persistent inequities in access.^[40] According to One Health Trust, improved vaccine coverage in LMICs could yield substantial economic savings through reduced antibiotic consumption and decreased morbidity burden.^[40] These data reinforce the socioeconomic case for embedding vaccines within AMR action plans, particularly in resource-limited settings. Similarly, the WHO identified that vaccines significantly reduce the quantities of antibiotics used and reduce healthcare expenditure linked to AMR.^[39] An estimate by One Health Trust found that improved vaccine coverage could yield important economic savings, both in terms of reduced antibiotic consumption and decreased morbidity burden related to resistance, mainly in LMICs.^[40] Vaccine equity challenges in LMICs are connected with the socioeconomic and geographic marginalization of smallholder farmers who depend on livestock as part of their livelihoods. Many of the 600–900 million poor livestock keepers in Africa, Asia, and Latin America face high animal disease burdens, with limited access to vaccines or veterinary services.^[41] Many LMICs cannot produce their own vaccines; they rely on external sources and, as a result, they are significantly affected by vaccine nationalism, hoarding, and instabilities in global supply chains. In manufacturing, national regulatory agencies play a crucial role in ensuring product safety, effectiveness, and quality in LMICs. The rapid expansion of vaccine manufacturing in these nations without adequate regulatory capacity may lead to poor product quality and adverse health outcomes, thereby significantly undermining public health systems. [Figure 5] outlines a multi-tiered framework of therapeutic strategies targeting AMR across individual, One Health, and global domains. It emphasizes how tailored interventions from species-specific antibiotics and vaccine development to global regulatory reform intersect to shape AMR outcomes. This figure anchors the translational narrative by positioning therapeutics as both clinical tools and policy levers within integrated health systems.^[42]

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Figure 5:

Therapeutic approaches to reduce the burden of antibiotic resistance.

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ONE HEALTH AND INTEGRATED APPROACHES

The integration of human, animal, and environmental vaccination strategies is essential in combating AMR through a One Health approach. This holistic framework recognizes the interconnectedness of these domains and emphasizes the need for coordinated interventions to mitigate AMR effectively. Vaccination in humans and animals reduces the incidence of infections, thereby decreasing the reliance on antibiotics. For instance, vaccines against pathogens like S. aureus in livestock can lower the need for antimicrobial treatments.^[43] The One Health framework promotes collaboration among human, veterinary, and environmental health sectors, facilitating the development and distribution of vaccines that address AMR across all domains.^[44,45] Effective vaccination strategies require supportive policies that encourage research and development (R&D) of vaccines, alongside antimicrobial stewardship (AMS) programs.^[46] Despite these benefits, several limitations moderate vaccine impact on AMR. Vaccine hesitancy (VH) remains a barrier to uptake, particularly in LMICs.^[39] Coldchain fragility undermines distribution in resourcelimited settings.^[32] Pathogen variability may also affect vaccine efficacy, though evidence shows burden reduction even in rare cases of vaccine resistance.^[6,24-26] Addressing these barriers through innovation and equitable access is essential to maximize vaccine contributions to AMR reduction. Environmental dimensions are equally critical within the One Health framework. Wastewater AMR surveillance provides early warning of resistant pathogens circulating in communities, while soil microbiome monitoring captures the ecological impacts of antibiotic use and vaccine interventions.^[5,39] Integrating these environmental tools alongside human and livestock vaccination strengthens AMR control by addressing transmission routes beyond clinical and agricultural settings.

The COVID-19 pandemic has underscored the need for robust AMR surveillance systems and stewardship programs, revealing vulnerabilities in existing healthcare frameworks. By leveraging lessons learnt during the pandemic, stakeholders can enhance AMR management through coordinated efforts that integrate surveillance and stewardship. Effective AMR management requires a synergy between AMS and surveillance, ensuring that data informs treatment guidelines and policy decisions.^[47] The development and dissemination of guidelines based on surveillance data can optimize antimicrobial use and reduce resistance.^[48] Many regions, particularly in Africa, face challenges such as poor clinical care and lack of robust surveillance systems, which hinder effective AMR management.^[49] Therefore, there is a significant need for improved diagnostic tools and education to bridge gaps in AMR stewardship and surveillance.^[49] While the integration of stewardship and surveillance presents a promising avenue for combating AMR, it is essential to address the systemic challenges that persist, particularly in low-resource settings. This dual approach must be supported by global policies and funding to ensure sustainable progress against AMR.

The role of AMR in zoonotic spillover prevention is critical, particularly as zoonotic diseases pose significant public health threats. Surveillance of wildlife, particularly bats, has revealed the presence of clinically significant resistant bacteria, such as methicillin-resistant S. aureus and colistin-resistant Enterobacteriaceae, which can facilitate zoonotic spillover events.^[50,51] The prevalence of AMR varies significantly based on geographic location and bat species, indicating the need for localized surveillance efforts to identify potential spillover risks.^[52] Effective prevention of zoonotic spillover requires collaboration across disciplines, integrating veterinary, medical, and environmental sciences to develop comprehensive strategies.^[52] Raising public awareness about AMR and its implications for zoonotic diseases is crucial for fostering responsible antimicrobial use and reducing spillover risks.^[52] Understanding the factors that facilitate spillover, such as inter-species interactions and environmental drivers, can guide targeted interventions to reduce spillover frequency.^[53] [Figure 6] illustrates how vaccines operate across human, animal, and environmental domains within the One Health framework. It emphasizes their role in reducing antibiotic demand, blocking zoonotic transmission, and preventing resistant microbes from circulating between sectors. By visually linking biomedical, ecological, and policy dimensions, the figure reinforces vaccines as central, cross-sectoral interventions against AMR.

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Figure 6:

One Health framework for vaccines in antimicrobial resistance.

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CLINICAL AND PUBLIC HEALTH IMPLICATIONS

Integrating vaccines into AMR strategies is increasingly recognized as a vital component in combating the global health crisis posed by AMR. Vaccines prevent infections caused by resistant pathogens, reducing the overall burden of AMR.^[54,55] By decreasing infection rates, vaccines lower antibiotic prescriptions, which is crucial in mitigating resistance development.^[56,57] Vaccination can create herd immunity, further protect unvaccinated populations, and reduce the spread of resistant strains.^[57] There is a call for vaccines to be formally recognized in national immunization strategies and AMR action plans.^[54,55] Strengthening collaborations between public and private sectors can enhance vaccine development and distribution.^[54] Increasing public awareness and addressing VH are essential for improving vaccination coverage, particularly in developing countries.^[57,58] Many LMICs have established national action plans and legislative policies aimed at controlling antibiotic use; however, enforcement remains weak. For instance, while 72% of LMICs have prescription requirements, 74% report that antibiotics can still be obtained without prescriptions.^[59] A significant proportion of countries lack monitoring systems for antibiotic use, with only 10% reporting such measures.^[59]

There is a pressing need to integrate antibiotic stewardship and bioethics into medical education. A study highlighted that medical professionals often lack understanding of AMR social implications, which hampers effective policy implementation.^[60] While the integration of vaccines into AMR strategies is promising, challenges remain, such as ensuring equitable access to vaccines and overcoming barriers to vaccination in various populations. Addressing these issues is crucial for maximizing the potential of vaccines in the fight against AMR. Strengthening routine immunization is a crucial strategy in controlling AMR, as vaccines can significantly reduce the incidence of infections that often lead to antibiotic use. By preventing these infections, vaccines help decrease the reliance on antibiotics, thereby reducing the opportunity for resistance to develop. This approach is particularly important given the global threat posed by AMR, which is projected to cause up to 10 million deaths annually by 2050 if left unchecked.^[56,20] [Table 4] consolidates public health interventions across human, animal, environmental, policy, research, and education sectors, showing how vaccines directly reduce AMR. It demonstrates that regular vaccination programs lower resistant infections in humans, veterinary vaccines minimize antibiotic use in livestock, and biosafety practices prevent environmental contamination. Policy frameworks, innovative vaccine platforms, and public education campaigns further embed vaccination into One Health AMR strategies, underscoring vaccines as both biomedical and societal tools for sustainable resistance control.^[29,61-71]

CHALLENGES AND FUTURE DIRECTIONS

The challenge that the scientific community faces is having limited data on the vaccine-AMR impact. Resistance to newly developed drugs can emerge within short time frame like decade,^[73] and few new antibiotics are currently in the pipeline, exacerbating the problem.^[74] Vaccines have been identified as an innovative tool for lowering infection rates and transmission of antibiotic-resistant pathogens.^[62] Although numerous interacting mechanisms have been proposed to explain how vaccines may curb antibiotic resistance,^[78,79] these complexities highlight the challenges of predicting the overall benefits of vaccination in controlling antibiotic-resistant pathogens. A well-defined method for understanding the complex interactions between hosts, pathogens, and their environment is mathematical modeling. Mathematical models of infectious disease mechanisms have been employed to comprehend and predict the impact of both vaccination and AMR.^[77,78] These models can quantify the factors controlling the acquisition and transmission of antibiotic resistance and predict the protective effect of vaccines on their hosts and the population. In addition, these models can be integrated easily within economic frameworks to foretell the economic costs and benefits which can be attributed to antibiotic resistance and vaccination. The establishment of the cost-effectiveness of interventions can assist policy decision-making about funding for control of antibiotic resistance and vaccination programs. Despite the fact that vaccines are very effective tools that are used to reduce the incidence of infectious diseases and usage of antibiotics, they are still far from reaching their full potential. There are still several infectious diseases for which no effective vaccine is available (e.g., Malaria, TB, HIV), as well as groups at risk with poor immune responses to current vaccines such as the infants, immune-compromised individuals, and the elderly.^[78] Therefore, new vaccines need to be in the pipeline; we should consider amplifying and improving the effects of current vaccines through the use of metabolic and epigenetic modulators. These approaches improve the efficacy of vaccines and may eventually potentiate the responses triggered by vaccines in immunocompromised individuals.^[78] Going forward, collaborations between scientists in R&D, governments, students, policy makers, and data analysts should be fostered to come up with vaccine designs for next-generation vaccines that can assist in the eradication of some infections, which in turn will reduce the rates of AMR. The One Health framework can also enhance vaccine-based solutions to mitigate AMR by integrating human, animal, and environmental Health. Vaccination lowers infection rates across species, thereby reducing the need for antibiotics and limiting the emergence and spread of resistant microbes. In livestock, vaccines decrease antibiotic usage, thereby minimizing residues and resistant microbes to penetrate the food chain or environment. Coordinated surveillance and cross-sector collaboration strengthen AMR prevention. Thus, vaccines serve as a sustainable One Health tools which protect Health holistically beyond antibiotics. The research for effective vaccines should begin with problem identification throughout to impact assessment and surveillance. [Figure 7] outlines the strategic research directions needed to advance vaccine innovation against AMR. It highlights next-generation platforms such as mRNA, viral vectors, and thermostable formulations, while emphasizing cross-species applicability and zoonotic transmission control. By mapping innovation priorities, the figure complements [Table 4]^[70-72] and underscores the role of research in sustaining One Health solutions to AMR.

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Figure 7:

Research roadmap for vaccine-antimicrobial resistance innovation.

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CONCLUSION

Vaccines stand at the intersection of biomedical innovation, public health policy, and socioeconomic equity, offering a unique pathway to mitigate the global burden of AMR. Unlike antibiotics, which act therapeutically and exert selective pressure on pathogens, vaccines operate prophylactically, reducing infection incidence and thereby lowering the demand for antimicrobials. This distinction makes vaccines not only powerful tools for individual protection but also systemic interventions that safeguard communities, livestock, and ecosystems. Their role extends beyond clinical outcomes to encompass food safety, environmental stewardship, and economic resilience, particularly in LMICs where AMR disproportionately impacts health systems and livelihoods. The One Health framework underscores the necessity of integrating vaccination strategies across human, animal, and environmental domains. Evidence demonstrates that vaccines reduce resistant infections in humans, minimize antibiotic use in livestock, and prevent environmental contamination through biosafety practices. Yet, challenges such as VH, coldchain fragility, and pathogen variability must be addressed through innovation, regulatory strengthening, and equitable access. Embedding vaccines into national AMR action plans and stewardship programs ensures that these barriers are systematically confronted, while maximizing the preventive and cost-effective potential of vaccines. In conclusion, vaccines represent durable, cross-sectoral interventions that protect Health holistically beyond antibiotics, making them indispensable catalysts for One Health solutions to AMR. Beyond these broad benefits, vaccines can be systematically integrated into AMS programs. By reducing inappropriate antibiotic prescriptions, lowering infection incidence, and strengthening herd immunity, vaccines complement stewardship goals. National initiatives such as the WHO Global Action Plan on AMR and the European Vaccination Action Plan have embedded vaccination within stewardship frameworks, showing measurable reductions in antibiotic use.^[39,67] Regionally, pneumococcal conjugate vaccine programs in subSaharan Africa have reduced MDR S. pneumoniae infections,^[29,62] while livestock vaccination campaigns in Denmark and Canada have lowered prophylactic antibiotic use.^[28,29] These examples demonstrate that vaccines are not stand-alone interventions but can be woven into AMS programs to deliver durable, cross-sectoral reductions in AMR burden. This paper presents a multidimensional synthesis of AMR mechanisms and therapeutic strategies, integrating molecular insights with translational and policy-level perspectives. Key learned moments include the recognition of AMR as a cross-sectoral challenge requiring coordinated action across individual, One Health, and global domains; the strategic value of vaccine development and resistance inhibitors in curbing MDR strains; and the imperative for equitable access and regulatory reform to support innovation. The schematic frameworks [Figures 3-5] anchor these insights by linking mechanistic understanding to clinical outcomes, health system responses, and global policy imperatives. Collectively, these highlights underscore the need for integrated, context-aware interventions to advance AMR control and therapeutic innovation. Ultimately, vaccines must be recognized not only as biomedical innovations but also as pillars of sustainable AMR control. Their integration into stewardship frameworks, supported by policy, education, and innovation, offers a pragmatic and equitable path toward safeguarding global Health.