Why does drug resistance readily evolve but vaccine resistance does not?

Abstract

Why 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.

Keywords: antimicrobial resistance; evolutionary rescue; pathogen evolution; vaccine escape.

Figure 1.

Time to first detection of human pathogens resistant to vaccines [–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.

Figure 2.

Schematic showing the effect of treatment timing on the evolution of resistance in a single infection. The dotted black line shows the pathogen population size over the course of an infection in an untreated host. The dashed black horizontal line shows the pathogen population size necessary for transmission. Dots mark the start of treatment, with red depicting early treatment (nearly prophylactic) and blue depicting later treatment (therapeutic). In comparison with later treatment, pathogen population size is small at the start of early treatment, reducing the likelihood that resistance will be generated de novo. In addition, when treatment is started sufficiently early, the sensitive pathogen population size (solid red curve) may never approach the threshold necessary for transmission and that might remain true even with small or moderate increases in resistance (dashed red curve). When treatment is started later, however, the sensitive pathogen (solid blue curve) may already be capable of transmission, so that small or moderate increases in resistance (dashed blue curve) would likely extend the window of time that the pathogen is transmissible. This creates a window of opportunity for partial resistance to be selectively favoured during spread to other hosts (shaded blue interval) that is not present when treatment begins early.