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, 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.</jats:p

Multistrain Models of Recombinant Transmissible Vaccines with Mutational Decay

In the absence of gene flow, populations undergo local adaptation to their environment. Swamping occurs when migrant genes prevent local adaptation with high levels of gene flow. Although swamping is often depicted as a problem, it could be implemented to arrest unwanted evolution in GMOs which depend on the integrity of transgenes. In GMO vaccines, the fitness cost of carrying an antigen results in reversion to virulence or antigenic decay through a series of mutational steps. Zoonotic diseases pose an increasing threat to people, causing an estimated 2.7 million worldwide human deaths each year. Recombinant transmissible vaccines (RTVs) provide a way to reduce the risk of infectious diseases, especially zoonotic diseases with wildlife reservoirs that cannot be directly vaccinated. A well-documented two-strain SIR model, including pathogen and RTV, represents the situation where an RTV can mutate to its vector in one step. We built an n-strain model expanding upon this model by imagining a similar situation where the RTV must undergo n-1 mutations, rather than one, to revert to the vector. Although the vector is benign, it competes with the RTV for susceptible individuals, thereby reducing the benefits of the RTV. We found that the level of direct vaccination necessary depends on mutation rate and the decline in efficacy from each mutational step. This model allows us to quantify the amount of swamping in order to protect populations against infectious disease and prevent local adaptation

Nuclear weapons, the United States and alliances in Europe and Asia: Toward an institutional perspective

America’s alliances in Europe and East Asia all involve some institutional cooperation on U.S. nuclear weapons policy, planning or employment—from consultative fora in Asia to joint policy and sharing of nuclear warheads in NATO. Such cooperation is often analyzed through the prism of “extended nuclear deterrence,” which focuses on the extension of U.S. security guarantees and their effect on potential adversaries. This article argues that this underplays the importance of institutional factors: Allies have historically addressed a range of objectives through such cooperation, which has helped to catalyze agreements about broader alliance strategy. The varied form such cooperation takes in different alliances also flows from the respective bargaining power of allies and the relative importance of consensus, rather than perceived threats. The article concludes that nuclear weapons cooperation will remain crucial in successful U.S. alliance management, as allies negotiate their relationship with each other in the face of geostrategic change.No Full Tex