Vaccines against Antibiotic Resistance: an update: Comparison
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Please note this is a comparison between Version 4 by Dean Liu and Version 3 by Giovanni Nicola Roviello.

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 90s has progressively diminished, and many of them correspond to slight modifications of existing drugs. Apart from the difficulties in developing new effective antimicrobials, the worrying scenario of the antimicrobial resistance (AMR) recalls the urgent need of new strategies to fight the bacterial infections. Among the others, vaccination is a winning solution to the problem of the  AMR, at least in the context of some of the most common pathogenic bacteria as we aim to summarize in this work.

  • vaccines
  • antibiotics
  • pathogens
  • infectious diseases
  • antimicrobial resistance

1. Challenges in Developing New Antibiotics

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 90s has progressively diminished, and many of them correspond to slight modifications of existing drugs [1],[2]. The search for new antimicrobials is challenging, and this can be due to several factors, which are mainly classifiable as scientific and commercial difficulties [3].
The first challenge that companies and investigators have to face in the development of lead molecules is the need for compounds that are effective in inactivating or killing bacteria through specific processes. The results obtained by GlaxoSmithKline (GSK), which evaluated more than 300 bacterial genes and performed about 70 high throughput screenings from 1995 to 2001, were very disappointing, with a success rate lower than 10% [4]. Similar results were reported by several other profitable companies, including AstraZeneca, and huge research costs have been sustained without any satisfactory outcomes.
Moreover, optimizing the antimicrobial effect of lead molecules constitutes a task that is not easy to achieve. In the case of Gram-negative pathogens, for example, an effective antimicrobial is expected to penetrate the outer membrane and the cell wall of the bacteria to reach the intracellular target and exert the desired effect. These layers are endowed with different properties and lipophilicity, which makes the design and realization of a desirable compound particularly difficult. Not less importantly, the designed drug should be able to avoid the bacterial efflux pump, a mechanism by which the drug could be pumped out from the bacteria without reaching the target [3].
Another difficulty is represented by the optimization of the safe and tolerable properties of a drug. This is usually a very prolonged process that is affected by different factors. In the case of antimicrobials, adverse events are a major safety concern, with antibiotics being implicated in ∼20% of all drug-related emergency department visits, as reported in studies conducted in the United States [5]. Most of these visits are due to allergic reactions accounting for 79% of all the adverse effects of antibiotics; however, other conditions, including gastrointestinal, psychiatric, and/or neurologic symptoms are also associated with antimicrobials [5]. The chemical nature of the compound, is reconsidered and modified when a safety issue is observed during a lead identification program, causing further time and cost consumption. In addition to these concerns, the conduction of clinical trials to test antimicrobials in vivo is generally hampered by several factors. For example, the recruitment of new patients involved in clinical trials requires that they have not been treated with antimicrobials 24 h before starting the trial. However, this often represents an insurmountable barrier as some patients, especially those with advanced pneumonia, need to assume antibiotics as soon as possible in order to reach high survival rates. As a consequence, the clinical study is greatly delayed [3].
Among the major challenges stalling new antimicrobial development, it is also worth mentioning the lack of funding needed to support expensive clinical trials, but even more importantly, of a market interested in newly licensed antibiotic drugs [6]. To overcome these difficulties, there is an urgent need for commitment to national funding and international coordination on this theme. Sadly, governments of many countries are reluctant to invest significant resources in the fight against antimicrobial resistance that they see as an issue that is not solely their own. On the other hand, low-resource countries, where AMR has the highest burdens, have fragile economic conditions that do not let them lead the reform of the antimicrobials discovery and market [6].

2. Effect of Vaccines on AMR

Hence, other strategies aimed at fighting AMR have been proposed [7]. Among these, vaccines may be the key to limiting the spread of resistant pathogens and the consequent AMR. Vaccines have represented an important achievement in the field of immunology since their implementation in the prophylaxis therapy of patients worldwide contributes significantly to the prolongation of life expectancy. The importance of vaccination has recently emerged with the COVID-19 pandemic, for which the fast development of safe and efficient vaccination was an urgent necessity [8],[9].
After vaccination, the resulting production of antibodies is specific to eradicate a certain pathogen for a time whose length depends on the type of vaccine, and this immune response is different among individuals. 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 [10]. As a proof of concept, the effect of vaccination against Streptococcus in the USA reduced by 84% the cases of Streptococcus pneumonia caused by multidrug resistance in children younger than 2 years of age  [11]. While an antibiotic is designed against a specific target, vaccines are directed against multiple targets, which makes resistance episodes in the vaccinated population very rare. In fact, more mutations conferring resistance are needed if multiple immunogenic epitopes are exposed [7]. Additionally, the duration of the protection and the herd immunity, if reached, make the vaccines more efficient and reliable tools than antibiotics. According to the above-mentioned study [11], vaccination reduced the transmission of Streptococcus pneumonia in unvaccinated 65-year-old people by 49%. Even in the rare case of a resistance to vaccines, such as the three examples reported by Kennedy and Read [12], two of which involved vaccination against bacterial pathogens (Streptococcus pneumonia and Bordetella pertussis), a severe outcome of the disease is still avoided due to the preventive nature of vaccines. On the contrary, the antimicrobial therapeutic effect is completely blocked in the case of resistance to antibiotic drugs [10], [12].
Famously, vaccines permitted the eradication of smallpox [13] and rinderpest virus [14], almost eliminated poliomyelitis, and significantly contributed to reducing the incidence of other diseases, including pertussis, tetanus, and diphtheria [15].
The reason why vaccination can be a successful strategy for the treatment of AMR lies in the evidence that vaccines can directly restrain the spread of resistant pathogens through specific antibodies, thus minimizing or avoiding the usage of antibiotics. Such effects have been well documented with Haemophilus influenzae type b, Pneumococci, meningococci, and Rotavirus vaccines [16]. According to a clinical trial carried out in 2018 on 6–35 months 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 prescription [17].
Similar results were obtained in Ontario, where the vaccination of children against influenza led to a 64% reduced antibiotic prescription with respect to other provinces of Canada [18]. An indirect effect of vaccines is to prevent secondary bacterial infections, such as pneumonia and otitis, which can easily occur following viral infection. By inhibiting secondary infections after vaccination, the inappropriate consumption of antibiotics is averted. As described in a single-blind study by Ozgur et al., 119 Turkish children who underwent influenza vaccination experienced a significant reduction in acute otitis media, otitis media with effusion, and total otitis compared to the unvaccinated group, confirming the usefulness of vaccination in preventing secondary infections [19].

3. Current Vaccines in Preclinical and Clinical Development

In their work, Micoli et al. listed the antimicrobial-resistant pathogens described as critical by the World health organization (WHO) and Centers for Disease Control and Prevention (CDC), together with the diseases they cause and the antibiotics to which they have developed resistance [7]. On 12 July 2022, the first report on the pipeline of vaccines in the course of development to mitigate the AMR has been published by WHO, stating that the clinical trials of last-stage development vaccines should be speeded up, and the implementation of existing vaccines boosted (https://www.who.int/news/item/12-07-2022-urgent-call-for-better-use-of-existing-vaccines-and-development-of-new-vaccines-to-tackle-amr accessed on 9 December 2022). This report describes not only vaccines in preclinical and clinical development but also failed candidates. Moreover, it classifies pathogens into different groups according to the feasibility expressed as the progression of the candidate vaccine in clinical trials, its biological as well as product development feasibility, and access and implementation feasibility. The biological feasibility takes into account factors including immunity from natural exposure and the likelihood of a vaccine to protect against most pathogenic strains. On the other hand, the product development feasibility relies on the availability of in vivo and in vitro models to assist vaccine development, the set-up of a late-stage clinical test, and the usage of human models, if required. Access and implementation feasibility refer to the possibility of easily introducing novel vaccine candidates in a target population, such as through children’s vaccination programs, by means of commercial incentives and political transparency. Pseudomonas aeruginosa, Klebsiella pneumoniae, Extraintestinal pathogenic Escherichia coli (ExPEC), Acinetobacter baumannii, and Enterotoxigenic Escherichia coli (ETEC), which were listed as critical priority pathogens, have shown 4, 5, 4, 5, and 10 vaccine candidates, respectively. For Staphylococcus aureus, a high-priority pathogen, there were 14 candidates. The highest number of candidates (20), however, has been found in the case of Mycobacterium tuberculosis, which is a well-established priority pathogen. The numbers mentioned above refer to preclinical analyses carried out in 2021, where a total of 94 candidates were confirmed, (https://www.who.int/news/item/12-07-2022-urgent-call-for-better-use-of-existing-vaccines-and-development-of-new-vaccines-to-tackle-amr accessed on 9 December 2022). A total of 61 candidate vaccines were confirmed in active clinical trials. S. pneumonia and M. tuberculosis have the highest number of candidates (16 and 13, respectively). K. pneumoniae and Neisseria gonorrhoeae both have one candidate vaccine. Instead, no vaccine candidates have been identified for P. aeruginosa, Helicobacter pylori, Campylobacter jejuni, Enterobacter spp., Enterococcus faecium, and A. baumannii . Remarkably, the high and critical-priority pathogens tend to show fewer vaccine candidates compared to the medium-priority ones both in preclinical and clinical trials. Vaccines against Shigella sonnei and H. pylori have been discontinued, reflecting a common issue of vaccine production represented by economic, logistic, and scientific obstacles.
As above-mentioned, a classification of pathogens according to the feasibility of vaccine candidates and their development state has been created. Group A includes pathogens for which a vaccine has been licensed, while pathogens with vaccine candidates in clinical trials belong to group B. Group C and D include, respectively, feasible pathogens but with challenges in targeting the vaccine and pathogens with low feasibility in vaccine production (https://www.who.int/news/item/12-07-2022-urgent-call-for-better-use-of-existing-vaccines-and-development-of-new-vaccines-to-tackle-amr accessed on 9 December 2022).

3. Conclusions

Today, the use of antibiotics is a revolutionary weapon against several infectious diseases and has contributed to save millions of lives worldwide. However, the misuse of these drugs is fueling the antimicrobial resistance process, now considered a global emergency by the World Health Organization, with a worrying increase of the risk of deaths especially in the clinical settings and of the consequent health care costs. Current research to develop new effective antibiotics is extremely challenging and only a few effective candidates have been identified recently due to difficulties associated with AMR. Therefore, new therapeutic or preventive strategies to combat AMR are urgently needed. In this scenario, vaccines represent a promising approach that has proven crucial to preventing the spread of pathogens in primary infections and in minimizing the use of antibiotics after secondary bacterial infections[20]. Unfortunately, due to pathogen complexity and technical challenges, most of the vaccines developed against major resistant pathogens are still in preclinical and clinical trials but the research on this prophylactic antimicrobial strategy is very promising and full of potential. 

References

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