The Potential Beneficial Effects of Vaccination on Antigenically Evolving Pathogens.

AbstractAlthough vaccines against antigenically evolving pathogens such as seasonal influenza ; and are designed to protect against circulating strains by affecting the emergence and transmission of antigenically divergent strains, they might in theory also be able to change the rate of antigenic evolution. Vaccination might slow antigenic evolution by increasing immunity, reducing the overall prevalence or population size of the pathogen. This reduction could decrease the supply and growth rates of mutants and might thereby slow adaptation. But vaccination might accelerate antigenic evolution by increasing the transmission advantage of more antigenically diverged strains relative to less diverged strains (i.e., by positive selection). Such evolutionary effects could affect vaccination's direct benefits to individuals and indirect benefits to the host population (i.e., the private and social benefits). To investigate these potential impacts, we simulated vaccination against a continuously circulating influenza-like pathogen in a simple population. On average, more vaccination decreased the incidence of infection. Notably, this decrease was driven partly by a vaccine-induced decline in the rate of antigenic evolution. To understand how the evolutionary effects of vaccines might affect their social and private benefits, we fitted linear panel models to simulated data. By slowing evolution, vaccination increased the social benefit and decreased the private benefit. Thus, vaccination's potential social and private benefits may differ from current theory, which omits evolutionary effects. These results suggest that conventional vaccines against influenza and other antigenically evolving pathogens, if protective against transmission and given to the appropriate populations, could further reduce disease burden by slowing antigenic evolution.

Criteria to make animal studies more relevant to treating human cancer.

Certain aspects of experimental tumor models in mice most accurately reflect the biology and immunology of cancer in patients. A survey of experimental cancer immunotherapy papers published in 2020 shows most do not achieve cancer shrinkage although treatment is initiated at an early time point after cancer cell injection, which does not reflect cancer immunotherapy in patients. Even then, few current experimental approaches eradicate the injected malignant cells, most only delay outgrowth. The value of targeting mutation-encoded tumor-specific antigens becomes increasingly evident while problems of finding normal gene-encoded tumor-associated antigens as safe, effective targets persist. It might be time to refocus on realistic experimental settings and truly cancer-specific targets. These antigens are associated with the least risk of side effects.

Estimating Vaccine-Driven Selection in Seasonal Influenza.

Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some ("targeted") strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for vaccine-induced selection in influenza by comparing strain frequencies between more and less vaccinated human populations. We defined strains in three ways: first as influenza types and subtypes, next as lineages of type B, and finally as clades of influenza A/H3N2. We detected spatial differences partially consistent with vaccine use in the frequencies of subtypes and types and between the lineages of influenza B, suggesting that vaccines do not select strongly among all these phylogenetic groups at regional scales. We did detect a significantly greater frequency of an H3N2 clade with known vaccine escape mutations in more vaccinated countries during the 2014⁻2015 season, which is consistent with vaccine-driven selection within the H3N2 subtype. Overall, we find more support for vaccine-driven selection when large differences in vaccine effectiveness suggest a strong effect size. Variation in surveillance practices across countries could obscure signals of selection, especially when strain-specific differences in vaccine effectiveness are small. Further examination of the influenza vaccine's evolutionary effects would benefit from improvements in epidemiological surveillance and reporting.

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth.

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords "immunotherapy" AND "cancer" for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5-121 mm(3) in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm(3) was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm(3), and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm(3), and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth.