The impact of human vaccines on bacterial antimicrobial resistance. A review

Abstract

At present, the dramatic rise in antimicrobial resistance (AMR) among important human bacterial pathogens is reaching a state of global crisis threatening a return to the pre-antibiotic era. AMR, already a significant burden on public health and economies, is anticipated to grow even more severe in the coming decades. Several licensed vaccines, targeting both bacterial (Haemophilus influenzae type b, Streptococcus pneumoniae, Salmonella enterica serovar Typhi) and viral (influenza virus, rotavirus) human pathogens, have already proven their anti-AMR benefits by reducing unwarranted antibiotic consumption and antibiotic-resistant bacterial strains and by promoting herd immunity. A number of new investigational vaccines, with a potential to reduce the spread of multidrug-resistant bacterial pathogens, are also in various stages of clinical development. Nevertheless, vaccines as a tool to combat AMR remain underappreciated and unfortunately underutilized. Global mobilization of public health and industry resources is key to maximizing the use of licensed vaccines, and the development of new prophylactic vaccines could have a profound impact on reducing AMR.

Keywords: Antibiotic resistance; Bacterial vaccine; Herd immunity; Human vaccination; Multidrug resistance; Viral vaccine.

Fig. 1

Molecular mechanisms of action for antibiotics compared to vaccines. a Antibiotics either kill bacteria (bactericidal) or stop them from growing (bacteriostatic) by four main mechanisms: preventing DNA/RNA synthesis; preventing folate synthesis, which prevents nucleic acid synthesis; destroying the cell wall/membrane; and targeting ribosomes to prevent protein synthesis. Antibiotic resistance mechanisms neutralize the mechanism of action for the antibiotic. Resistance mechanisms can be acquired through horizontal transfer from plasmids and other genetic elements donated by bacteria that are co-localized with the pathogen. Alternatively, resistance can occur through vertical transmission via chromosomal mutations. These resistance mechanisms include the expression of enzymes such as the β-lactamases which inactivate the antibiotics (β-lactams); the expression or overexpression of efflux pumps which remove the antibiotic from the bacteria; the modification of the target so that it is no longer susceptible to the antibiotic; and using bypass mechanisms to circumvent antibiotic toxicity, including modification of the cell surface to prevent antibiotic entry or direct modification of antibiotics to prevent target engagement (Kohanski et al. ; Levy and Marshall 2004). b In contrast to antibiotics, vaccines exert their action via immune pathways, eliciting antigen specific polyclonal antibodies that can either neutralize bacterial virulence factors such as toxins or adhesins, or engage effector arms to kill the bacteria through mechanisms including the complement cascade or opsonophagocytic uptake into phagocytes (Forthal 2014). ROS, reactive oxygen species. Copyright [Kathrin U. Jansen, William C. Gruber, Raphael Simon, James Wassil, and Annaliesa S. Anderson] 2021

Fig. 2

Antibiotic resistance levels associated with major bacterial pathogens across the globe. Data shown are from 2000 to 2014 and represent the percentage of isolates (the range) tested that are resistant to each antibiotic class used for each pathogen (pathogen specific), not taking into account the proportion of strains that are resistant to more than one antibiotic class. ROS: reactive oxygen species. For all pathogens except M. tuberculosis and N. gonorrhoeae, data were obtained from the Center for Disease Dynamics, Economics & Policy (https://resistancemap.cddep.org). For M. tuberculosis, data were obtained from WHO Drug Resistant TB Surveillance & Response—Supplement: Global Tuberculosis Report 2014 (World Health Organization 2014a). For N. gonorrhoeae, data were obtained from the World Health Organization Global Gonococcal Antimicrobial Surveillance Program which covers strains analyzed between 2011 and 2014 (http://www.who.int/reproductivehealth/topics/rtis/gonococcal_resistance/en/). ND, no data provided. Copyright [Kathrin U. Jansen, William C. Gruber, Raphael Simon, James Wassil, and Annaliesa S. Anderson] 2021

Fig. 3

Reduction of antimicrobial resistance after broad rollout of PCV13. Data presented show average annual rates of antibiotic nonsusceptible invasive pneumococcal disease (IPD) of the vaccine- and non-vaccine type, with standard deviations in (a) vaccinated (children younger than 5 years) and (b) non-vaccinated (adults 65 years of age and older) populations, prior to (2005–2009) and following (2011–2013) introduction of PCV13 vaccine. Adapted from (Tomczyk et al. 2016). Copyright [Kathrin U. Jansen, William C. Gruber, Raphael Simon, James Wassil, and Annaliesa S. Anderson] 2021