Designing transmissible viral vaccines for evolutionary robustness and maximum efficiency

Abstract

The danger posed by emerging infectious diseases necessitates the development of new tools that can mitigate the risk of animal pathogens spilling over into the human population. One promising approach is the development of recombinant viral vaccines that are transmissible, and thus capable of self-dissemination through hard to reach populations of wild animals. Indeed, mathematical models demonstrate that transmissible vaccines can greatly reduce the effort required to control the spread of zoonotic pathogens in their animal reservoirs, thereby limiting the chances of human infection. A key challenge facing these new vaccines, however, is the inevitability of evolutionary change resulting from their ability to self-replicate and generate extended chains of transmission. Further, carrying immunogenic transgenes is often costly, either in terms of metabolic burden, increased competition with the pathogen, or due to unintended interactions with the viral host regulatory network. As a result, natural selection is expected to favor vaccine strains that down-regulate or delete these transgenes resulting in increased rates of transmission and reduced efficacy against the target pathogen. In addition, efficacy and evolutionary stability will often be at odds; as when longer, more efficacious antigens experience faster rates of evolutionary decay. Here we ask how such trade-offs influence the overall performance of transmissible vaccines. We find that evolutionary instability can substantially reduce performance, even for vaccine candidates with the ideal combination of efficacy and transmission. However, we find that, at least in some cases, vaccine stability and overall performance can be improved by the inclusion of a second, redundant antigen. Overall, our results suggest that the successful application of recombinant transmissible vaccines will require consideration of evolutionary dynamics and epistatic effects, as well as basic measurements of epidemiological features.

A non-transmissible live attenuated SARS-CoV-2 vaccine

“…Unintentional spread of vaccine viruses from vaccinated to unvaccinated individuals can complicate the use of transmissible live attenuated vaccines (LAVs). 1 , 2 , 3 , 4 While self-dissemination is desirable in some scenarios, specifically when herd immunity is sought in wildlife, 5 uncontrolled circulation of vaccine viruses potentially increases the risk of reversion to virulence. 2 , 3 , 4 Recombination between different vaccine viruses or vaccine and field viruses is particularly problematic because it can give rise to recombinants with increased virulence, transmissibility, or immune evasion capabilities.…”

Longitudinal deep sequencing informs vector selection and future deployment strategies for transmissible vaccines

“…A remaining uncertainty, however, is that natural selection is expected to purge antigenic inserts from viral vectors. Although techniques to reduce the loss of inserts are advancing [ 27 ], this phenomenon has potential to create competition between circulating vaccine strains and “ex-vaccine” strains that have reverted to wild type and may have a fitness advantage over remaining vaccine strains [ 28 ].…”

Quantifying the effectiveness of betaherpesvirus-vectored transmissible vaccines

“…At the same time, however, other studies have suggested superinfection is much more challenging ( 30 – 32 ) and may be achievable only by genetically differentiated MCMV strains. If superinfection requires genetic divergence, transmissible vaccines constructed from locally common betaherpesvirus strains or constructed in a way that results in the rapid loss of their immunogenic cargo are unlikely to succeed ( 15 , 16 , 33 ). Second, our inferences drawn from wild populations assume the geographic distribution of MCMV prevalence represents an equilibrium state and that differences in equilibrium prevalence thus reflect location specific transmission rates.…”

“…Although previous modeling efforts have demonstrated the potential benefits of vaccine transmission ( 9 , 13 – 17 ), these models have been general and not parameterized for specific candidate vaccine vectors or zoonotic pathogens. Further, existing models have focused almost exclusively on steady-state solutions and have not addressed the timescale over which zoonotic pathogens can be eliminated.…”