Why does drug resistance readily evolve but vaccine resistance does not? | Proceedings of the Royal Society of London B: Biological Sciences

but vaccine resistance does not?David A. Kennedy, Andrew F. ReadPublished 29 March 2017.DOI: 10.1098/rspb.2016.2562ArticleFigures & DataInfo & MetricseLetters PDFAbstractWhy is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced.1. IntroductionPathogen evolution impacts the efficacy of vaccines and antimicrobial drugs (e.g. antibiotics, antivirals, antimalarials) very differently (figure 1). After a new drug is introduced, drug resistance can rapidly evolve, leading to treatment failures [12]. For instance, most Staphylococcus aureus isolates in British hospitals were resistant to penicillin just 6 years after the introduction of the drug [13]. Similar evolutionary trajectories have been observed for the vast majority of drugs [14] and today many drugs are clinically useless against particular pathogens [15]. The problem has become so acute that drug resistance is viewed as one of the great challenges of our age, ranking alongside climate change and surpassing terrorism [16]. By striking contrast, vaccines generally provide sustained disease control. Most human vaccines have continued to provide protection since their introduction decades or even centuries ago (figure 1). For example, smallpox was eradicated because no virus strains capable of transmitting between vaccinated individuals ever emerged [17]. Indeed, the evolution of vaccine resistance is so rare that vaccines are now considered a leading solution to the drug resistance problem [11,18].Download figureOpen in new tabDownload powerpointFigure 1.Time to first detection of human pathogens resistant to vaccines [1–6] and antimicrobial drugs [7]. Similar patterns exist for antiviral drugs, although antiviral resistance evolution can often be slowed by the use of combination antiviral therapy [8,9]. Viral vaccines are labelled in purple, bacterial vaccines are labelled in green. Blue ‘x’s denote the first observations of resistance, with lines starting at product introduction (except for smallpox vaccination which began much earlier). Note that in all cases, substantial public health gains continued to accrue beyond the initial appearance of resistance. Only vaccines in the current immunization schedule recommended by the Centers for Disease Control and Prevention [6] are shown, with the addition of the smallpox vaccine. Global eradication of smallpox (marked as a filled, blue circle), ended the opportunity for resistance to emerge (blue line). The seasonal influenza vaccine is routinely undermined by antigenic evolution, evolution that occurs even in the absence of vaccination (dotted line). We took the earliest appearance of a vaccine-resistant pertussis variant to be the first record of a pertactin-negative strain [5]. This date [10] and several others (e.g. [11]) could be debated, but the general pattern is robust: resistance to drugs occurs more readily than resistance to vaccines.Yet drugs and vaccines both profoundly suppress pathogen fitness and so both should generate tremendous evolutionary pressure for resistance (defined here as a phenotype conferring increased pathogen replication or survival in treated hosts). Why then does pathogen evolution regularly undermine drug efficacy but rarely undermine vaccine efficacy (figure 1)? Here we propose that well-known principles of resistance management explain why vaccine resistance rarely evolves.Note that we restrict our discussion to evolutionary changes that result either from mutation or from amplification of extremely rare variants (those maintained by mutation-selection balance). This focus excludes cases of ‘common-variant serotype replacement’ in which strains of a pathogen that were previously observed but intentionally not targeted by vaccines rise in frequency after the onset of vaccination. Although serotype replacement is a form of evolution, and an important consideration in a vaccinated host population, this process is perhaps better explained by purely ecolog

Source: Why does drug resistance readily evolve but vaccine resistance does not? | Proceedings of the Royal Society of London B: Biological Sciences


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