Impact of waning immunity against SARS-CoV-2 severity exacerbated by vaccine hesitancy.

The SARS-CoV-2 pandemic has generated a considerable number of infections and associated morbidity and mortality across the world. Recovery from these infections, combined with the onset of large-scale vaccination, have led to rapidly-changing population-level immunological landscapes. In turn, these complexities have highlighted a number of important unknowns related to the breadth and strength of immunity following recovery or vaccination. Using simple mathematical models, we investigate the medium-term impacts of waning immunity against severe disease on immuno-epidemiological dynamics. We find that uncertainties in the duration of severity-blocking immunity (imparted by either infection or vaccination) can lead to a large range of medium-term population-level outcomes (i.e. infection characteristics and immune landscapes). Furthermore, we show that epidemiological dynamics are sensitive to the strength and duration of underlying host immune responses; this implies that determining infection levels from hospitalizations requires accurate estimates of these immune parameters. More durable vaccines both reduce these uncertainties and alleviate the burden of SARS-CoV-2 in pessimistic outcomes. However, heterogeneity in vaccine uptake drastically changes immune landscapes toward larger fractions of individuals with waned severity-blocking immunity. In particular, if hesitancy is substantial, more robust vaccines have almost no effects on population-level immuno-epidemiology, even if vaccination rates are compensatorily high among vaccine-adopters. This pessimistic scenario for vaccination heterogeneity arises because those few individuals that are vaccine-adopters are so readily re-vaccinated that the duration of vaccinal immunity has no appreciable consequences on their immune status. Furthermore, we find that this effect is heightened if vaccine-hesitants have increased transmissibility (e.g. due to riskier behavior). Overall, our results illustrate the necessity to characterize both transmission-blocking and severity-blocking immune time scales. Our findings also underline the importance of developing robust next-generation vaccines with equitable mass vaccine deployment.

Assessing immune phenotypes using simple proxy measures: promise and limitations.

The study of immune phenotypes in wild animals is beset by numerous methodological challenges, with assessment of detailed aspects of phenotype difficult to impossible. This constrains the ability of disease ecologists and ecoimmunologists to describe immune variation and evaluate hypotheses explaining said variation. The development of simple approaches that allow characterization of immune variation across many populations and species would be a significant advance. Here we explore whether serum protein concentrations and coarse-grained white blood cell profiles, immune quantities that can easily be assayed in many species, can predict, and therefore serve as proxies for, lymphocyte composition properties. We do this in rewilded laboratory mice, which combine the benefits of immune phenotyping of lab mice with the natural context and immune variation found in the wild. We find that easily assayed immune quantities are largely ineffective as predictors of lymphocyte composition, either on their own or with other covariates. Immunoglobulin G (IgG) concentration and neutrophil-lymphocyte ratio show the most promise as indicators of other immune traits, but their explanatory power is limited. Our results prescribe caution in inferring immune phenotypes beyond what is directly measured, but they do also highlight some potential paths forward for the development of proxy measures employable by ecoimmunologists.

Andrea L. Graham.

Interview with Andrea Graham, who studies the ecological and evolutionary causes of immunological heterogeneity in mammals at Princeton University.

Genetic and environmental interactions contribute to immune variation in rewilded mice.

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

Immune response of the Almaco jack (Seriola rivoliana) against the infestation with Neobenedenia sp. in three cultivated temperatures.

The Almaco jack (Seriola rivoliana) is a marine fish maintained in mariculture systems and frequently infested by monogenean parasites like Neobenedenia sp. Severe infestations can lead to high mortalities and economic losses for farmers. This study evaluated the effects of temperature on the immune response on Almaco jack infested with Neobenedenia sp. We exposed infested fishes at temperatures of 20 °C, 24 °C, and 30 °C for 20 days and took samples of different tissues at the beginning of the experiment, and after 3 and 20 days. The tissues considered were the skin, thymus, cephalic kidney, and spleen to evaluate the relative gene expression of different genes: Hsp70, IgM, IL-1ß, IL-10, and MyD88. Our results showed an increase in IL-1ß gene expression in the skin after 20 days of infestation but no significant effect of temperature on gene expression, despite increases in infestation rates with temperature. Therefore, relative genetic expression was controlled by the number of parasites and the days post-infestation. These results show that the parasite infestation induced a local response in the skin, but that temperature has an indirect effect on the immune system of Almaco jack.

Spatiotemporal-social association predicts immunological similarity in rewilded mice.

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.

Demographic, environmental and physiological predictors of gastrointestinal parasites in urban raccoons.

Raccoons are host to diverse gastrointestinal parasites, but little is known about the ecology of these parasites in terms of their interactions with each other during coinfections, their interactions with host physiology and environmental factors, and their impact on raccoon health and survival. As a first step, we investigated the patterns of parasite infection and their demographic distribution in an urban-suburban population of raccoons trapped in the summers and autumns of 2018 and 2019. We collected faecal samples, demographic data, morphometric measurements, and blood smears, and used GPS data to classify trapping location by land cover type. Faecal floats were performed to detect and quantify gastrointestinal nematode eggs and coccidia oocysts, and white blood cell differentials were performed on blood smears to characterise white blood cell distributions. Data were analysed cross-sectionally and, where possible, longitudinally, using generalised linear models. Overall, 62.6% of sampled raccoons were infected with gastrointestinal nematodes, and 82.2% were infected with gastrointestinal coccidia. We analysed predictors of infection status and faecal egg count for three different morphotypes of nematode-Baylisascaris, strongyle, and capillariid nematodes-and found that infection status and egg count varied with Year, Month, Age class, Land cover, and coinfection status, though the significance of these predictors varied between nematode types. Gastrointestinal coccidia prevalence varied with Year, Month, Age class, strongyle infection status, and capillariid infection status. Coccidia oocyst counts were lower in adults and in October, but higher in females and in raccoons trapped in areas with natural land cover; furthermore, coccidia oocysts were positively associated with capillariid faecal egg counts. We found no evidence that gastrointestinal parasites influenced raccoon body condition or overwinter mortality, and so conclude that raccoons, though harbouring diverse and abundant gastrointestinal parasites, may be relatively tolerant of these parasites.

serosim: An R package for simulating serological data arising from vaccination, epidemiological and antibody kinetics processes.

serosim is an open-source R package designed to aid inference from serological studies, by simulating data arising from user-specified vaccine and antibody kinetics processes using a random effects model. Serological data are used to assess population immunity by directly measuring individuals' antibody titers. They uncover locations and/or populations which are susceptible and provide evidence of past infection or vaccination to help inform public health measures and surveillance. Both serological data and new analytical techniques used to interpret them are increasingly widespread. This creates a need for tools to simulate serological studies and the processes underlying observed titer values, as this will enable researchers to identify best practices for serological study design, and provide a standardized framework to evaluate the performance of different inference methods. serosim allows users to specify and adjust model inputs representing underlying processes responsible for generating the observed titer values like time-varying patterns of infection and vaccination, population demography, immunity and antibody kinetics, and serological sampling design in order to best represent the population and disease system(s) of interest. This package will be useful for planning sampling design of future serological studies, understanding determinants of observed serological data, and validating the accuracy and power of new statistical methods.

Medium-term scenarios of COVID-19 as a function of immune uncertainties and chronic disease.

As the SARS-CoV-2 trajectory continues, the longer-term immuno-epidemiology of COVID-19, the dynamics of Long COVID, and the impact of escape variants are important outstanding questions. We examine these remaining uncertainties with a simple modelling framework that accounts for multiple (antigenic) exposures via infection or vaccination. If immunity (to infection or Long COVID) accumulates rapidly with the valency of exposure, we find that infection levels and the burden of Long COVID are markedly reduced in the medium term. More pessimistic assumptions on host adaptive immune responses illustrate that the longer-term burden of COVID-19 may be elevated for years to come. However, we also find that these outcomes could be mitigated by the eventual introduction of a vaccine eliciting robust (i.e. durable, transmission-blocking and/or 'evolution-proof') immunity. Overall, our work stresses the wide range of future scenarios that still remain, the importance of collecting real-world epidemiological data to identify likely outcomes, and the crucial need for the development of a highly effective transmission-blocking, durable and broadly protective vaccine.

Challenges in cybersecurity: Lessons from biological defense systems.

Defending against novel, repeated, or unpredictable attacks, while avoiding attacks on the 'self', are the central problems of both mammalian immune systems and computer systems. Both systems have been studied in great detail, but with little exchange of information across the different disciplines. Here, we present a conceptual framework for structured comparisons across the fields of biological immunity and cybersecurity, by framing the context of defense, considering different (combinations of) defensive strategies, and evaluating defensive performance. Throughout this paper, we pose open questions for further exploration. We hope to spark the interdisciplinary discovery of general principles of optimal defense, which can be understood and applied in biological immunity, cybersecurity, and other defensive realms.

Rewilding of laboratory mice enhances granulopoiesis and immunity through intestinal fungal colonization.

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component ß-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.

Genetic and Environmental interactions contribute to immune variation in rewilded mice.

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite, Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

On maternity and the stronger immune response in women.

Medical research reports that women often exhibit stronger immune responses than men, while pathogens tend to be more virulent in men. Current explanations cannot account for this pattern, creating an obstacle for our understanding of infectious-disease outcomes and the incidence of autoimmune diseases. We offer an alternative explanation that relies on a fundamental difference between the sexes: maternity and the opportunities it creates for transmission of pathogens from mother to child (vertical transmission). Our explanation relies on a mathematical model of the co-evolution of host immunocompetence and pathogen virulence. Here, we show that when there is sufficient vertical transmission co-evolution leads women to defend strongly against temperate pathogens and men to defend weakly against aggressive pathogens, in keeping with medical observations. From a more applied perspective, we argue that limiting vertical transmission of infections would alleviate the disproportionate incidence of autoimmune diseases in women over evolutionary time.

The evolution of powerful yet perilous immune systems.

The mammalian immune system packs serious punch against infection but can also cause harm: for example, coronavirus disease 2019 (COVID-19) made headline news of the simultaneous power and peril of human immune responses. In principle, natural selection leads to exquisite adaptation and therefore cytokine responsiveness that optimally balances the benefits of defense against its costs (e.g., immunopathology suffered and resources expended). Here, we illustrate how evolutionary biology can predict such optima and also help to explain when/why individuals exhibit apparently maladaptive immunopathological responses. Ultimately, we argue that the evolutionary legacies of multicellularity and life-history strategy, in addition to our coevolution with symbionts and our demographic history, together explain human susceptibility to overzealous, pathology-inducing cytokine responses. Evolutionary insight thereby complements molecular/cellular mechanistic insights into immunopathology.

Optimal immune specificity at the intersection of host life history and parasite epidemiology.

Hosts diverge widely in how, and how well, they defend themselves against infection and immunopathology. Why are hosts so heterogeneous? Both epidemiology and life history are commonly hypothesized to influence host immune strategy, but the relationship between immune strategy and each factor has commonly been investigated in isolation. Here, we show that interactions between life history and epidemiology are crucial for determining optimal immune specificity and sensitivity. We propose a demographically-structured population dynamics model, in which we explore sensitivity and specificity of immune responses when epidemiological risks vary with age. We find that variation in life history traits associated with both reproduction and longevity alters optimal immune strategies-but the magnitude and sometimes even direction of these effects depends on how epidemiological risks vary across life. An especially compelling example that explains previously-puzzling empirical observations is that depending on whether infection risk declines or rises at reproductive maturity, later reproductive maturity can select for either greater or lower immune specificity, potentially illustrating why studies of lifespan and immune variation across taxa have been inconclusive. Thus, the sign of selection on the life history-immune specificity relationship can be reversed in different epidemiological contexts. Drawing on published life history data from a variety of chordate taxa, we generate testable predictions for this facet of the optimal immune strategy. Our results shed light on the causes of the heterogeneity found in immune defenses both within and among species and the ultimate variability of the relationship between life history and immune specificity.

Vaccine nationalism and the dynamics and control of SARS-CoV-2.

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of "vaccine nationalism," we extend previous models to include simple scenarios of stockpiling between two regions. In general, when vaccines are widely available and the immunity they confer is robust, sharing doses minimizes total cases across regions. A number of subtleties arise when the populations and transmission rates in each region differ, depending on evolutionary assumptions and vaccine availability. When the waning of natural immunity contributes most to evolutionary potential, sustained transmission in low-access regions results in an increased potential for antigenic evolution, which may result in the emergence of novel variants that affect epidemiological characteristics globally. Overall, our results stress the importance of rapid, equitable vaccine distribution for global control of the pandemic.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

Given vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two critical issues arise: How timing of delivery of the second dose will affect infection dynamics and how it will affect prospects for the evolution of viral immune escape via a buildup of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose as compared with natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short term, focusing on one dose generally decreases infections, but that longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose and to ramp up vaccination efforts globally.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.

Naturalizing mouse models for immunology.

Laboratory mice have provided invaluable insight into mammalian immune systems. Yet the immune phenotypes of mice bred and maintained in conventional laboratory conditions often differ from the immune phenotypes of wild mammals. Recent work to naturalize the environmental experience of inbred laboratory mice-to take them where the wild things are (to borrow a phrase from Maurice Sendak), via approaches such as construction of exposure histories, provision of fecal transplants or surrogate mothering by wild mice, and rewilding-is poised to expand understanding, complementing genetic and phylogenetic research on how natural selection has shaped mammalian immune systems while improving the translational potential of mouse research.