Could the human papillomavirus vaccines drive virulence evolution?

Abstract

The human papillomavirus (HPV) vaccines hold great promise for preventing several cancers caused by HPV infections. Yet little attention has been given to whether HPV could respond evolutionarily to the new selection pressures imposed on it by the novel immunity response created by the vaccine. Here, we present and theoretically validate a mechanism by which the vaccine alters the transmission-recovery trade-off that constrains HPV's virulence such that higher oncogene expression is favoured. With a high oncogene expression strategy, the virus is able to increase its viral load and infected cell population before clearance by the vaccine, thus improving its chances of transmission. This new rapid cell-proliferation strategy is able to circulate between hosts with medium to high turnover rates of sexual partners. We also discuss the importance of better quantifying the duration of challenge infections and the degree to which a vaccinated host can shed virus. The generality of the models presented here suggests a wider applicability of this mechanism, and thus highlights the need to investigate viral oncogenicity from an evolutionary perspective.

Keywords: human papillomavirus; oncogenes; transmission–recovery trade-off; virulence evolution; within-host model.

Figure 1.

Time-series of unvaccinated within-host model for various oncogene expression levels. Warm to cool colours represent time-series runs for different ɛ values from 0 to 1. Lower ɛ gives slower growth of Y₁ and Y₂ (e.g. orange–red). Note that Y₁ and Y₂ infected cells produce the V curves. The invasion of Z is delayed at lower levels of ɛ; thus faster growth of Y₂, due to higher ɛ, leads to faster clearance.

Figure 2.

Time-series of vaccinated within-host model for various oncogene expression levels. At lower levels of oncogene expression, the virus is cleared effectively by the CTL (decay of Y₁, Y₂ and V for ɛ < 0.7), but if higher, then viral load increases due to an increase in self-dividing infected cells. Note that Z appears at the same time regardless of oncogene expression. The range of ɛ shown is from 0 to 1.2.

Figure 3.

Unvaccinated host plots. (a) V_total of both immunocompetent and immunodeficient hosts. The ɛ* that is selected for by within-host processes is low, which demonstrates that recovery is the cost to rapid growth inside the host. Immunodeficient hosts can select for a slightly higher optimal oncogene expression. Unvaccinated immunodeficient parameters: ω = 0.0001, Z₀ = 10⁻⁵. (b) R₀ with respect to oncogene expression for various sexual behaviours. Immunocompetent only. Superspreaders (yellow) and individuals with casual partnerships (purple) have higher R₀ values (maximum) above the average (short partnerships, red), and individuals with long partnerships (blue) are below 1. Including the sexual behaviour model does not change the ɛ* away from the within-host optimal, thus all three groups select for the same ɛ*. Vaccinated host plots. (c) V_total of both immunocompetent and immunodeficient hosts. No maximum is achieved, instead higher oncogene expression allows for higher viral loads. Immunodeficient hosts have steeper curves implying they reach higher viral loads with lower ɛ values. Vaccinated immunodeficient parameters: ω = 0.01, Z₀ = 10⁻⁵. (d) R₀ with respect to oncogene expression for various sexual behaviours. Immunocompetent only. The ɛ-values where the curves cross R₀ = 1 is the minimum value of ɛ needed for the virus to circulate, . Superspreaders need a lower oncogene expression to maintain circulation of the virus than casual and short partnerships (higher on purple and red curves, respectively). Long partnerships (blue) do not rise fast enough to cross R₀ = 1.

Figure 4.

Effect of vaccine humoral response on optimal epsilon. Sexual behaviour groups: superspreaders (yellow), casual (purple) and short (red). (a) The oncogene expression needed for persistent circulation, , with respect to the strength of the antibody response, δ_vac. Generally, increases with a stronger humoral response. Note that above each line are ɛ values that can also circulate (with R₀ values more than 1). (b) The derivative at for various δ_vac. The strength of selection for higher epsilon is stronger in immunodeficient hosts (dashed lines) in both casual and superspreader groups. Higher δ_vac implies slower selection towards . (c) The effect of vaccine-induced clearance time on optimal epsilon. Each line represents the oncogene expression needed for persistent circulation, , in a particular sex group, thus the shaded region above represents ɛ values that have R₀ values higher than 1. The oncogene expression needed for in the vaccinated host depends on how quickly vaccine-induced clearance happens. At Z₀ = 10⁻⁴, the vaccinated host sheds virus for about 150 days, and at Z₀ = 1 the vaccinated host shed the virus for 50 days. For all three sexual behaviour groups, if the challenge infection is cleared quickly (high Z₀) then a higher is favoured, but if the infection is cleared in under 50 days then even high oncogene expression cannot help the virus from escaping the vaccine.