Evaluating the promise of recombinant transmissible vaccines

Abstract

Transmissible vaccines have the potential to revolutionize infectious disease control by reducing the vaccination effort required to protect a population against a disease. Recent efforts to develop transmissible vaccines focus on recombinant transmissible vaccine designs (RTVs) because they pose reduced risk if intra-host evolution causes the vaccine to revert to its vector form. However, the shared antigenicity of the vaccine and vector may confer vaccine-immunity to hosts infected with the vector, thwarting the ability of the vaccine to spread through the population. We build a mathematical model to test whether a RTV can facilitate disease management in instances where reversion is likely to introduce the vector into the population or when the vector organism is already established in the host population, and the vector and vaccine share perfect cross-immunity. Our results show that a RTV can autonomously eradicate a pathogen, or protect a population from pathogen invasion, when cross-immunity between vaccine and vector is absent. If cross-immunity between vaccine and vector exists, however, our results show that a RTV can substantially reduce the vaccination effort necessary to control or eradicate a pathogen only when continuously augmented with direct manual vaccination. These results demonstrate that estimating the extent of cross-immunity between vector and vaccine is a critical step in RTV design, and that herpesvirus vectors showing facile reinfection and weak cross-immunity are promising.

Recombinant vector vaccines and within-host evolution

“…The potential for attenuated viruses to revert to wild-type virulence is well appreciated [1,2], even if it presents a problem for relatively few vaccines (e.g., attenuated polio: [40]). There is also a potential for live, recombinant vector vaccines to evolve – our focus in this paper – with the main concern being loss or reduced expression of the transgenic insert [4,41]. If the vaccine evolution occurs fast enough or the vaccine infection persists long enough, loss of the insert could reduce vaccine efficacy.…”

Controlling epidemics with transmissible vaccines

“…In addition to the obvious negative consequences of such reversion at the individual level, reversion to wild type would effectively introduce the pathogen into the target population prematurely, thus reducing the population level benefits of vaccine transmission. In contrast, evolution in recombinant vector vaccines may result in reversion to free vector, resulting in competition with the vaccine [ 12 ], and reducing the benefits of vaccine transmission.…”

“…In such cases, unwanted evolution may pose more of a logistical challenge than risk. Specifically, transmissible recombinant vector vaccines require that the antigenic insert be stably maintained in the replicating vector population in the face of inevitable selection favoring mutations to the insert free state [ 12 ]. Overcoming this engineering challenge may prove to be a more significant obstacle to the development of transmissible vaccines than the evolution of increased virulence.…”

“…Thus, we study the best-case scenario where the vaccine leads to perfect, lifelong pathogen immunity. Although we do not specify the type of transmissible vaccine (i.e., attenuated vs. recombinant vector), our model applies to both as long as natural immunity to the vector is absent from the host population and reversion does not occur[ 12 ]. We focus our analyses on weakly transmissible vaccines with a basic reproductive number less than one ( R 0, v < 1) because they minimize opportunities for evolution[ 13 ] and stutter to extinction when direct vaccination is ceased.…”

Evolution and containment of transmissible recombinant vector vaccines

“…A transmissible vaccine works on the same principles as other live vaccines—following administration to an individual, the vaccine leads to stimulation of a protective immune response—but with its capacity for transmission, the vaccine is able to spread and immunologically protect other susceptible individuals beyond those directly vaccinated. Results from mathematical modeling indicate that transmissible vaccines substantially increase vaccine coverage and thereby the scope for pathogen elimination or eradication (Basinski et al, ; Nuismer et al, ; Nuismer, May, Basinski, & Remien, ). To date, transmissible vaccines remain largely untested.…”