Antimicrobial drugs and vaccines are two types of human interventions that create an inhospitable environment for pathogens. Such inhospitable environment could itself in turn stoke the evolution of microbial resistance by facilitating the survival of mutants that could successfully evade these interventions and render them ineffective. However, crucial selection pressure differences between antimicrobials and vaccines make the latter far less likely to spur such resistance (also table below from 1).
- Direct (antimicrobial) versus indirect (vaccine) selection pressures.
- Act afterwards (therapeutic antimicrobial) versus beforehand (prophylactic vaccine) ➛ Larger (antimicrobial) versus smaller (vaccine) pathogen populations.
- Narrower (antimicrobial) versus broader (vaccine) targets ➛ Narrower (antimicrobial) versus broader (vaccine) agent.
Antimicrobials Impose Direct Selection Pressure On Pathogens While Vaccines Target Them Indirectly
An antimicrobial directly targets the pathogen whereas a vaccine targets it indirectly by inducing immune responses against itself. In turn such immune responses should effectively counter the pathogen if and when the body encounters it.
The ace in a vaccine’s hand is that it piggybacks on the body’s own immune system, which is an attribute that has evolved over evolutionary time to effectively surmount pathogenic challenges.
Not only that, immune responses vary between individuals, which means that where the pathogen may be able to evade immunity in one host, another host would be able to kill it (2). An antimicrobial is a one-trick pony by comparison, mediating its intervention similarly across hosts.
Antimicrobials Act Therapeutically On Expanded Populations Of Pathogens In Host While Vaccines Target Act Prophylactically On Host Immune System In Absence of Targeted Pathogens
Antimicrobials are given therapeutically to treat infections whereas vaccines are given prophylactically to prevent them.
- By the time an antimicrobial enters the body, the pathogen has already invaded and multiplied enough to induce disease symptoms.
- On the other hand, a vaccine (ideally) enters a healthy body either entirely devoid of that pathogen or harboring only a few members.
Therefore an antimicrobial acts on a larger microbial population. Rule of thumb is larger the population under selection pressure, higher the likelihood of successful mutants and therefore of antimicrobial resistance (1 , 3, 4).
Antimicrobials Target Microbes Narrowly, Stereotypically & Indiscriminately While Vaccines Stoke Immunity That Targets Specific Pathogens Broadly and Individually
An antimicrobial such as an antibiotic or an antiviral typically targets a specific molecule or related molecules important for the survival of a select microorganism or a group whereas a vaccine ideally induces a great variety of immune responses against various target sites of a specific pathogen.
- Narrow targets mean that one or few mutations suffice to get around an antimicrobial whereas many more mutations are necessary to evade the immune responses induced by a vaccine.
- Antimicrobials are also indiscriminate in that they’ll target pathogens as well as the commensal microbiota and in doing so, induce resistance mutations in both. This has a two-pronged deleterious effect,
- Mutations in bystander commensal microbiota populations can be easily transferred horizontally to pathogens that enter and exit their environment (5), which only serves to spread antimicrobial resistance beyond a specific host.
- Depletion of microbiota itself by antibiotics can harm both the immune system as well as the nutritional status of the individual (6).
These are some of the reasons why antimicrobial resistance showed up within the very initial years of antibiotic use whereas vaccine resistance is rare (below from 7).
Vaccine resistance is more likely when the vaccine contains few targets. For example, Hepatitis B and Streptococcus pneumoniae vaccines contain just one antigen (target) each while the newer pertussis vaccine used in wealthier countries such as the US is a simplified version containing a handful of antigens, unlike the vaccine used in countries such as India, which is the entire killed organism.
Irony about such trends is that newer, so-called ‘safer’ vaccines are a contradiction in terms since safety and immunogenicity, the ability to drive strong immune responses, are mutually exclusive goals. When regulators and vaccine makers in wealthier countries succumb to unrealistic anti-vaccine pressures that demand safer vaccines and develop newer vaccines that are simpler and less complex by design, less effective immunity ensues which in turn enables escape variants of the pathogen to develop and evade elimination (8 , 9). A vicious, self-defeating cycle if ever there was one.
Bibliography
1. Kennedy, David A., and Andrew F. Read. “Why does drug resistance readily evolve but vaccine resistance does not?.” Proceedings of the Royal Society B: Biological Sciences 284.1851 (2017): 20162562. https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016.2562
2. Nédélec, Yohann, et al. “Genetic ancestry and natural selection drive population differences in immune responses to pathogens.” Cell 167.3 (2016): 657-669. Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens
3. Orr, H. Allen, and Robert L. Unckless. “The population genetics of evolutionary rescue.” PLoS Genetics 10.8 (2014): e1004551. The Population Genetics of Evolutionary Rescue
4. Blair, Jessica MA, et al. “Molecular mechanisms of antibiotic resistance.” Nature reviews microbiology 13.1 (2015): 42. https://www.tu-braunschweig.de/Medien-DB/ifm/reviewantibioticresistance2014.pdf
5. Tedijanto, Christine, et al. “Estimating the proportion of bystander selection for antibiotic resistance among potentially pathogenic bacterial flora.” Proceedings of the National Academy of Sciences 115.51 (2018): E11988-E11995. https://www.pnas.org/content/pnas/115/51/E11988.full.pdf
6. Bloom, David E., et al. “Antimicrobial resistance and the role of vaccines.” Proceedings of the National Academy of Sciences 115.51 (2018): 12868-12871. https://www.pnas.org/content/pnas/115/51/12868.full.pdf
7. Kennedy, David A., and Andrew F. Read. “Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance.” Proceedings of the National Academy of Sciences 115.51 (2018): 12878-12886. https://www.pnas.org/content/pnas/115/51/12878.full.pdf
8. Gandon, Sylvain, et al. “Imperfect vaccines and the evolution of pathogen virulence.” Nature 414.6865 (2001): 751. https://www.era.lib.ed.ac.uk/bitstream/handle/1842/711/Read.pdf?sequence=2
9. Fleming-Davies, Arietta E., et al. “Incomplete host immunity favors the evolution of virulence in an emergent pathogen.” Science 359.6379 (2018): 1030-1033. Incomplete host immunity favors the evolution of virulence in an emergent pathogen