Can vaccines act as a mechanism to reduce antimicrobial resistance?

KEYWORDS:

• Vaccine
• antibiotics
• antimicrobial resistance
• pediatrics
• infectious disease

Antimicrobial resistance (AMR) is a global threat that affects not only human health, but also animal, agricultural and environmental health. In the United States, antibiotic resistance–the most ominous type of AMR–causes 8 million days of hospital stays and has a cost of 30 USD billion per year [1]. In some countries more than 35% of common human infections are already resistant to currently available medicines; and in low- and middle-income countries resistance rates can be as high as 90% for some antibiotic-bacterium combinations [2]. No new classes of antibiotics have been introduced in clinical practice since 1987 [3]. AMR is increasing and unless a substantial global response is initiated, it has been estimated that by 2050 10 million people will die every year due to AMR [4].

There are a number of well-established tools to reduce the global burden of AMR: sanitation and hygiene, development of new classes of antibiotics, antibiotic stewardship, education to avoid inappropriate antibiotic use in the treatment of viral infections, and elimination of routine antibiotics in livestock [5]. Vaccination has also been proposed as a tool to reduce the number of bacterial infections that need antibiotics, reduce the number of drug-resistant infections and reduce the number of viral infections that receive unnecessary antibiotics [6]. Resistant infections that can be prevented by vaccination are, by definition, a case for which AMR disease can be reduced, the need for antibiotic therapy eliminated, and the risk of poor outcome avoided [7]. Vaccines as a mean to combat AMR have been scarcely investigated and there are few modeling studies that aim to quantify the public health effect of vaccines on AMR [8].

First, we must address the issue of increasing vaccination coverage. The development of combined vaccines increases coverage while diminishing aversion to receiving multiple injections [9]. Other advances such as nanovaccines are being studied to further increase acceptance of vaccines while generating adequate protection [10]. Greater coverages mean greater direct and indirect protection.

Vaccines can be a key component in the fight against AMR, both directly and indirectly. Being directed against pathogens, vaccines directly reduce the need for antimicrobials. For example, the pneumococcal conjugate vaccine was developed to target the most virulent serotypes linked to pneumococcal disease and associated with antibiotic resistance [8]. According to the Centers for Disease Control and Prevention (CDC), the latest pneumococcal conjugate vaccine prevented more than 4,000 invasive infections and reduced by 62% the number of drug-resistant invasive infections in the US after only three years [11].

Other vaccines that can substantially help to reduce AMR are currently under development. We briefly mention several agents of AMR with promising vaccines in clinical trials [12]. Clostridioides difficile has become the principal causing agent of nosocomial diarrhea. Resistance to antibiotics for C. difficile has grown over the past 10 years, forcing the CDC to label C. difficile as an emergent threat [13]. At least three different clinical trials are being conducted using toxins to generate immunity against C. difficile, with the elderly as the intended target population [14]. One of the biggest concerns with C. difficile is the possibility that normal gut bacteria act as a reservoir for resistance genes. Normal bacteria con accumulate resistance genes from previous antibiotic exposures making a possible C. difficile infection more complicated to treat than previously thought [15].

Staphylococcus aureus is the principal cause of post-surgical nosocomial infections [16,17]. In 2018, Redi et al. reviewed multiple studies about the development of a vaccine. There exist more than 20 pre-clinical trials. However, no trails have completed phase III. S. aureus presents a great challenge in vaccine development due to the multiple antigens it possesses and the different pathologic pathways through which it generates disease [18]. Generating a vaccine would greatly impact community acquired and nosocomial infections.

Group B Streptococcus (GBS) presents a great risk to newborns who can develop severe complications if infected. More than 25% of expectant mothers take antibiotics for GBS. With penicillin allergies present in about 10% of the population, the use of macrolides has prompted macrolide-resistant strains [19]. Two clinical trials are underway to try to prevent this devastating infection.

Multidrug-resistant, untreatable strains of Neisseria gonorrhoeae have been reported. Due to the lack of new antibiotics to treat such an ailment the development of a vaccine could present itself as a solution to such a problem. Models have estimated a reduction of at least 90% of cases after 20 years if all 13 year-old were vaccinated [20].

After the November 2016 outbreak of resistant Salmonella in Pakistan it became evident the need to increase vaccination in endemic countries [21]. Current Salmonella vaccines have not been widely used due to its low immunogenicity and need to reapply every 2–5 years. By generating a vaccine that can prevent such a disease the reduction in use of antibiotics would greatly reduce the pressure that is currently generated to select antibiotic-resistant strains [22].

Vaccines against other bacteria such as Escherichia coli, Mycobacterium tuberculosis, as well as viruses such as respiratory syncytial virus are also currently under study [5], and will likely help fight AMR.

Another important development is the possibility of multiple target sites for immunity. The development of broad spectrum glycoconjugate vaccine for Klebsiella pneumoniae and Pseudomonas aeruginosa has proven to be a very interesting concept. Having multiple target sites in noscomial bacteria vaccines might reduce infections in a substantial amount by generating adequate immunogenicity [23].

Vaccines can also have an indirect effect that reduces AMR. Vaccination can reduce pathogenic bacteria by reducing the complications associated with super infections that usually require antibiotic use. Vaccines directed against viral pathogens reduce the incidence of these viral infections, reduce hospital and outpatient visits and therefore reduce the possibility of receiving antibiotics erroneously. Universal vaccination of the seasonal influenza vaccine was associated with a 64% decrease in antibiotic prescriptions compared to vaccination in specific population groups at risk [24]. Other studies have shown a positive impact in the reduction of antibiotics prescription, both in children and in adults vaccinated against influenza [25,26]. Additionally, less antivirals and antibiotics are used against influenza in vaccinated individuals, both as a treatment and as prophylaxis [27,28], preventing influenza AMR directly as well.

Another benefit of vaccines is that they reduce AMR by establishing herd immunity. Herd immunity is an added benefit that occurs when vaccines are administered in a large population. The vaccine not only protects individuals who receive it, but it prevents the transmission of the pathogen to unvaccinated susceptible individuals. A high vaccination coverage can protect individuals who cannot receive the vaccine, for example those immunocompromised or not old enough to receive the vaccine. The reduced number of infections, reduces antimicrobial use and thus also AMR. Significant reductions in AMR in all age groups have been documented after the introduction of pneumococcal vaccines in children all over the world [29].

To avert the current global AMR emergency, the control of AMR requires multiple strategies in prevention. Vaccines provide one of the safest ways to prevent AMR. Vaccines protect directly and indirectly against infections, reducing the need of antimicrobial treatments, especially the need of broad-spectrum antibiotics. The reduction in the use of antimicrobials reduces the pressure in selecting resistant agents. Unless the world acts urgently, antimicrobial resistance will have disastrous impact within a generation. We thus urge for a fast development of vaccines against the most common agents of AMR, as well as an increase in vaccination coverage of groups targeted by vaccines currently available.

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.

Acknowledgments

The author thanks Jorge A. Alfaro-Murillo who revised the manuscript and provided helpful suggestions to improve it. The author has 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.

Additional information

Funding

This paper was not funded.