Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance

Abstract

Vaccines and antimicrobial drugs both impose strong selection for resistance. Yet only drug resistance is a major challenge for 21st century medicine. Why is drug resistance ubiquitous and not vaccine resistance? Part of the answer is that vaccine resistance is far less likely to evolve than drug resistance. But what happens when vaccine resistance does evolve? We review six putative cases. We find that in contrast to drug resistance, vaccine resistance is harder to detect and harder to confirm and that the mechanistic basis is less well understood. Nevertheless, in the cases we examined, the pronounced health benefits associated with vaccination have largely been sustained. Thus, we contend that vaccine resistance is less of a concern than drug resistance because it is less likely to evolve and when it does, it is less harmful to human and animal health and well-being. Studies of pathogen strains that evolve the capacity to replicate and transmit from vaccinated hosts will enhance our ability to develop next-generation vaccines that minimize the risk of harmful pathogen evolution.

Keywords: HBV; Marek’s disease virus; Streptococcus; evolutionary rescue; pertussis.

Fig. 1.

Time between deployment of an intervention and the first documented failure in humans due to resistance (marked with “x”s). Different classes of antibiotic drugs are labeled in different colors. Viral vaccines are labeled in purple and bacterial vaccines are labeled in green. The circle for the smallpox vaccine denotes global eradication of the virus, which ended the opportunity for vaccine resistance to evolve. Influenza is shown as a dotted line to highlight that it is routinely changed in an attempt to match circulating virus strains. Note that serotype replacement is not shown. While many of the cases of antibiotic resistance and one case of vaccine resistance can be explained by horizontal gene transfer, horizontal gene transfer is not considered to be an important factor in the evolution of antimalarial, antitubercular, or antiviral drug resistance. Data for antimalarial drugs are from refs. –. Data for antibiotic drugs are from ref. . Data for vaccines are from refs. , , and –. Modified from ref. .

Fig. 2.

(A–D) Disease incidence before and after vaccine introductions for four of our case-study pathogens. Analogous data are unavailable for Y. ruckeri and avian metapneumovirus. All data reflect disease dynamics in the United States. Solid lines denote the approximate introduction of first-generation vaccines. Dashed and dotted lines denote the approximate introduction of second- and third-generation vaccines, respectively. Updates to the hepatitis B and pertussis vaccines were made in response to concerns of vaccine safety, not pathogen evolution. Disease dynamics are driven by many factors in addition to vaccines and vaccine resistance, and so not all declines in disease can be attributed to vaccination. We nevertheless note that in A–D, disease rates have never returned to prevaccination levels despite the emergence of vaccine resistance. Data in A–C are compiled from the Centers for Disease Control (–139). Data in D are compiled from the USDA Poultry Slaughter Reports (107).

Fig. 3.

Marek’s disease virus concentration in dust over time on two different broiler chicken farms where all birds were vaccinated against Marek’s disease (140). Infection is transmitted through inhalation of virus-contaminated dust, and so these plots show a proxy for force of infection over time. Birds were reared in discrete nonoverlapping cohorts within each farm. White intervals denote periods when birds were present, red intervals denote periods between chicken flocks when birds were absent, and blue intervals denote periods of no surveillance. Error bars show 95% confidence intervals. Vaccine protection is imperfect such that vaccinated birds may still become infected and transmit, although at reduced rates (141, 142). Even in the presence of vaccination (bivalent vaccination on these farms), the virus is able to amplify within some chicken flocks. Nevertheless, vaccination was effective in the sense that no mortality or production losses due to Marek’s disease were documented on either farm during the surveillance period. Reprinted from ref.. VCN, virus genome copy number.