Modeling the Population Level Effects of an HIV-1 Vaccine in an Era of Highly Active Antiretroviral Therapy

First generation HIV vaccines may have limited ability to prevent infection. Instead, they may delay the onset of AIDS or reduce the infectiousness of vaccinated individuals who become infected. To assess the population level effects of such a vaccine, we formulate a deterministic model for the spread of HIV in a homosexual population in which the use of highly active antiretroviral therapy (HAART) to treat HIV infection is incorporated. The basic reproduction number R ₀ is obtained under this model. We then expand the model to include the potential effects of a prophylactic HIV vaccine. The reproduction number R _f is derived for a population in which a fraction f of susceptible individuals is vaccinated and continues to benefit from vaccination. We define f ^* as the minimum vaccination fraction for which R _f ≤1 and describe situations in which it equals the critical vaccination fraction necessary to eliminate disease. When R ₀ is large or an HIV vaccine is only partially effective, the critical vaccination fraction may exceed one. HIV vaccination, however, may still reduce the prevalence of disease if the reduction in infectiousness is at least as great as the reduction in the rate of disease progression. In particular, a vaccine that reduces infectiousness during acute infection may have an important public health impact especially if coupled with counseling to reduce risky behavior.     

Impulsive Vaccination of an SEIRS Model with Time Delay and Varying Total Population Size

Pulse vaccination is an effective and important strategy for the elimination of infectious diseases. A delayed SEIRS epidemic model with pulse vaccination and varying total population size is proposed in this paper. We point out, if R* < 1, the infectious population disappear so the disease dies out, while if R _*; > 1, the infectious population persist. Our results indicate that a long period of pulsing or a small pulse vaccination rate is sufficient condition for the permanence of the model.     

Comparing epidemic tuberculosis in demographically distinct heterogeneous populations

There is wide variation in endemic tuberculosis (TB) levels between countries and we seek to identify possible causes of these differences. In this study we present an epidemiological model of Mycobacterium tuberculosis infection to investigate the effects of host genetics and demographic factors on epidemic TB. We discuss the general framework for this approach and present analytical results to identify important parameters affecting steady-state prevalence and incidence rates of TB disease. We then use numerical simulations of our model to observe the effects of a genetically susceptible subpopulation on TB disease dynamics at the population level. Finally, we simulate infection within a genetically heterogeneous population in two demographic settings: India (a typical population with high TB prevalence) and the USA (a typical population with low TB prevalence). Results show that changes in transmission parameters, the fraction of the population genetically susceptible to infection, and demographic factors strongly affect TB prevalence and incidence rates.     

Toxoplasma gondii α-amylase deletion mutant is a promising vaccine against acute and chronic toxoplasmosis

Individuals with inhibited immunity may develop lethal toxoplasmosis; thus, a safe and effective vaccine is urged to be developed. Toxoplasma gondii (T. gondii) α-amylase (α-AMY) is one of the enzymes responsible for starch digestion. In the present study, we first generated a ME49Δα-amy mutant and discovered that loss of α-AMY robustly grew in vitro but contributed to significant virulence attenuation in vivo. Therefore, we established a mouse model to explore the protective immunity of Δα-amy mutant against acute and chronic toxoplasmosis. The results indicated that the survival rates of short-term or long-term immunized mice re-infected with the tachyzoites of multiple T. gondii strains were nearly 100%. ME49Δα-amy not only could provide protective immunity against tachyzoites infection but also could resist the infection of tissue cysts. Furthermore, we detected that ME49Δα-amy vaccination could effectively eliminate the proliferation of parasites in mice and prevent the formation of cysts. The significant increases of Th1-type cytokines, Th2-type cytokines and specific total IgG and IgG subclasses (IgG2a and IgG1) confirmed efficiency of a combination of cellular and humoral immunity against infection. In conclusion, ME49Δα-amy attenuated strain can produce strong immune responses to provide efficient protection against toxoplasmosis, which signifies that ME49Δα-amy mutant may be a potential vaccine candidate.     

Seasonal dynamics and thresholds governing recurrent epidemics

Driven by seasonality, many common recurrent infectious diseases are characterized by strong annual, biennial and sometimes irregular oscillations in the absence of vaccination programs. Using the seasonally forced SIR epidemic model, we are able to provide new insights into the dynamics of recurrent diseases and, in some cases, specific predictions about individual outbreaks. The analysis reveals a new threshold effect that gives clear conditions for the triggering of future disease outbreaks or their absence. The threshold depends critically on the susceptibility S ₀ of the population after an outbreak. We show that in the presence of seasonality, forecasts based on the susceptibility S ₀ are more reliable than those based on the classical reproductive number R ₀ from the conventional theory.      

Transmission Dynamics of an Influenza Model with Vaccination and Antiviral Treatment

Vaccination and antiviral treatment are two important prevention and control measures for the spread of influenza. However, the benefit of antiviral use can be compromised if drug-resistant strains arise. In this paper, we develop a mathematical model to explore the impact of vaccination and antiviral treatment on the transmission dynamics of influenza. The model includes both drug-sensitive and resistant strains. Analytical results of the model show that the quantities ℛ _SC and ℛ _RC , which represent the control reproduction numbers of the sensitive and resistant strains, respectively, provide threshold conditions that determine the competitive outcomes of the two strains. These threshold conditions can be used to gain important insights into the effect of vaccination and treatment on the prevention and control of influenza. Numerical simulations are also conducted to confirm and extend the analytic results. The findings imply that higher levels of treatment may lead to an increase of epidemic size, and the extent to which this occurs depends on other factors such as the rates of vaccination and resistance development. This suggests that antiviral treatment should be implemented appropriately.     

Measuring impact of vaccination among wildlife: The case of bait vaccine campaigns for classical swine fever epidemic among wild boar in Japan

Understanding the impact of vaccination in a host population is essential to control infectious diseases. However, the impact of bait vaccination against wildlife diseases is difficult to evaluate. The vaccination history of host animals is generally not observable in wildlife, and it is difficult to distinguish immunity by vaccination from that caused by disease infection. For these reasons, the impact of bait vaccination against classical swine fever (CSF) in wild boar inhabiting Japan has not been evaluated accurately. In this study, we aimed to estimate the impact of the bait vaccination campaign by modelling the dynamics of CSF and the vaccination process among a Japanese wild boar population. The model was designed to estimate the impact of bait vaccination despite lack of data regarding the demography and movement of wild boar. Using our model, we solved the theoretical relationship between the impact of vaccination, the time-series change in the proportion of infected wild boar, and that of immunised wild boar. Using this derived relationship, the increase in antibody prevalence against CSF because of vaccine campaigns in 2019 was estimated to be 12.1 percentage points (95% confidence interval: 7.8–16.5). Referring to previous reports on the basic reproduction number (R₀) of CSF in wild boar living outside Japan, the amount of vaccine distribution required for CSF elimination by reducing the effective reproduction number under unity was also estimated. An approximate 1.6 (when R₀ = 1.5, target vaccination coverage is 33.3% of total population) to 2.9 (when R₀ = 2.5, target vaccination coverage is 60.0% of total population) times larger amount of vaccine distribution would be required than the total amount of vaccine distribution in four vaccination campaigns in 2019.     

Waterborne toxoplasmosis investigated and analysed under hydrogeological assessment: new data and perspectives for further research

We present a set of data on human and chicken Toxoplasma gondii seroprevalence that was investigated and analysed in light of groundwater vulnerability information in an area endemic for waterborne toxoplasmosis in Brazil. Hydrogeological assessment was undertaken to select sites for water collection from wells for T. gondii oocyst testing and for collecting blood from free-range chickens and humans for anti-T. gondii serologic testing. Serologic testing of human specimens was done using conventional commercial tests and a sporozoite-specific embryogenesis-related protein (TgERP), which is able to differentiate whether infection resulted from tissue cysts or oocysts. Water specimens were negative for the presence of viable T. gondii oocysts. However, seroprevalence in free-range chickens was significantly associated with vulnerability of groundwater to surface contamination (p < 0.0001; odds ratio: 4.73, 95% confidence interval: 2.18-10.2). Surprisingly, a high prevalence of antibodies against TgERP was detected in human specimens, suggesting the possibility of a continuous contamination of drinking water with T. gondii oocysts in this endemic setting. These findings and the new proposed approach to investigate and analyse endemic toxoplasmosis in light of groundwater vulnerability information associated with prevalence in humans estimated by oocyst antigens recognition have implications for the potential role of hydrogeological assessment in researching waterborne toxoplasmosis at a global scale.     

Estimating Maximum Possible Environmental Loading Amounts of Cryptosporidium parvum Attributable to Adult Beef Cattle

Populations of beef cattle represent a potential non-point source of environmental contamination for Cryptosporidium parvum if on-farm management practices fail to minimize transport from bovine manure to adjacent water sources. Characterizing this risk of contamination requires several parameters to be estimated, the most important being a valid and precise estimate of the oocyst loading rate per animal unit. The oocyst loading rate is defined in this study as the total number of oocysts excreted by a cohort of adult beef cows during a 24[emsp4 ]h period. We propose a methodology for estimating this parameter for low prevalent populations whereby the majority of individuals are test negative. Under specific degrees of confidence and at the population scale, this methodology generates estimates for maximal oocyst loading based on the sensitivity of the diagnostic test and the point prevalence and intensity of fecal shedding from a cross-sectional survey of the target population.Our cross-sectional survey on California beef cows generated a prevalence of infection of 1.1 % (6/557) and an intensity of oocyst shedding ranging from 219 to 5,491 oocysts/g, with a geometric mean of 835 oocysts/g from six positive cows. Negative binomial estimate of the percent recovery of the diagnostic assay was 0.235. Based on this percent recovery and using approximately 19.4[emsp4 ]mg of feces per assay, the DT₉₀ of our assay, defined as the concentration of oocysts at which our diagnostic assay had a 90 % probability of detecting one or more oocysts in a sample, was 755 oocyst/g feces. At a 95 % confidence level, the estimated maximum number of oocysts being excreted in the feces of California beef cows ranged from 4.8 to 14.4 oocysts/g feces/cow, or 7.7×10⁴ to 2.3×10⁵ oocysts/beef cow/day.     

The History of Toxoplasma gondii—The First 100 Years

ABSTRACT. In this paper the history of Toxoplasma gondii and toxoplasmosis is reviewed. This protozoan parasite was first discovered in 1908 and named a year later. Its medical importance remained unknown until 1939 when T. gondii was identified in tissues of a congenitally infected infant, and veterinary importance became known when it was found to cause abortion storms in sheep in 1957. The discovery of a T. gondii specific antibody test, Sabin–Feldman dye test in 1948 led to the recognition that T. gondii is a common parasite of warm‐blooded hosts with a worldwide distribution. Its life cycle was not discovered until 1970 when it was found that felids are its definitive host and an environmentally resistant stage (oocyst) is excreted in feces of infected cats. The recent discovery of its common infection in certain marine wildlife (sea otters) indicates contamination of our seas with T. gondii oocysts washed from land. Hygeine remains the best preventive measure because currently there is no vaccine to prevent toxoplasmosis in humans.     

Direct evidence of Toxoplasma-induced changes in serum testosterone in mice

Latent toxoplasmosis is known to influence the morphology of infected persons and also increases the probability of the birth of male offspring in both humans and mice. All these traits can be related to the observed differences in the concentration of testosterone between Toxoplasma-infected and Toxoplasma-free subjects. However, it is not possible to decide, using the Toxoplasma-human model, whether toxoplasmosis influences the level of testosterone in the infected host or whether individuals with different levels of testosterone vary in the probability of toxoplasma infection. Here we studied changes in the testosterone levels in the latent phase of toxoplasmosis in laboratory mice artificially infected with cystogenic but relatively virulent strain T38 of T. gondii. We observed decreased testosterone levels in both female and male mice with latent toxoplasmosis in comparison to uninfected controls (P = 0.001). The present results indicate that Toxoplasma infection changes the concentration of serum testosterone in mice and human rather than changed concentration of testosterone influences the probability of the Toxoplasma infection. It is possible that the decrease of testosterone is an adaptive mechanism of infected mice aimed to compensate toxoplasmosis-induced immunosuppression observed during latent Toxoplasma infection.     

Wolbachia effects in natural populations of Chorthippus parallelus from the Pyrenean hybrid zone

We evaluate for the first time the effect of Wolbachia infection, involving two different supergroups, on the structure and dynamics of the hybrid zone between two subspecies of Chorthippus parallelus (Orthoptera) in the Pyrenees. Wolbachia infection showed no effects on female fecundity or a slight increment in females infected by F supergroup, although in the last case it has to be well established. Cytoplasmic incompatibility (CI) is confirmed in crosses carried out in the field between individuals from a natural hybrid population. This CI, registered as the relative reduction in embryo production (s_h), was of s_h = 0.355 and s_h = 0.286 in unidirectional crosses involving B and F supergroups, respectively. CI also occurred in bidirectional crosses (s_h = 0.147) but with a weaker intensity. The transmission rates of the two Wolbachia strains (B and F) were estimated by the optimization of a theoretical model to reach the infection frequencies observed in certain population. To fit this scenario, both supergroups should present transmission rates close to 1. Further, we have simulated the infection dynamics, and hence, the capacity of Wolbachia to structure the population of the host insects and to affect to reproduction and genetic introgression in the hybrid zone. This represents a first example of the influence of Wolbachia in an insect natural hybrid zone.     

Hantavirus Transmission in Sylvan and Peridomestic Environments

We developed a compartmental model for hantavirus infection in deer mice (Peromyscus maniculatus) with the goal of comparing relative importance of direct and indirect transmission in sylvan and peridomestic environments. A direct transmission occurs when the infection is mediated by the contact of an infected and an uninfected mouse, while an indirect transmission occurs when the infection is mediated by the contact of an uninfected mouse with, for instance, infected soil. Based on population dynamics data and estimates of hantavirus decay in the two types of environments, our model predicts that direct transmission dominates in the sylvan environment, while both pathways are important in peridomestic environments. The model allows us to compute a basic reproduction number R ₀, which indicates whether the virus will be endemic or eradicated from the mouse population, in both an autonomous and a time-periodic model. Our analysis can be used to evaluate various eradication strategies.     

Sensitivity Analyses of a Population Projection Model of Ring-Necked Pheasants

Abstract A large literature exists on population dynamics of ring-necked pheasant (Phasianus colchicus) in North America, but there has not been an attempt to formulate a matrix model nor a sensitivity analysis of the relationships between vital rates and population finite growth rate (Λ) that can be used to guide management. We summarized demographic data available from a 5-year field study in Iowa, USA, collected in Kossuth County (low composition of perennial habitat) and Palo Alto County (high composition of perennial habitat) into a 2-stage (young and adult) matrix projection model. We estimated Λ₁ (the dominant eigenvalue of the deterministic matrix), the stable age distribution (ω), relative reproductive value vector (n̈), other demographic parameters, and Λ_iid, a bootstrap estimate of growth that includes interannual variation in life history parameters. We analyzed the relative importance of vital rates on population growth rate using sensitivity and elasticity of both matrix elements and lower-level parameters such as winter survival and nest success. We first characterized general life history using averaged data from both areas and all years that yielded Λ₁ = 1.086, and a stable stage distribution of. Minimum success of the initial nesting attempt (H₁) that would maintain Λ ≥ 1 under average conditions was estimated to be 42%. Changes in Λ₁ were most sensitive to survival of chicks during brood rearing (S_B), followed in importance by survival during the subsequent winter (S_W), followed by H₁. We followed the general analyses with analyses that helped us to focus on the differences in the landscapes of northwest Iowa. Λ_iid was ≥1 in only 9% of simulations of data from Kossuth whereas estimated Λ_iid was ≥1 in 88% of simulations from Palo Alto. Our analyses of the relative importance and interactions between S_B, S_W, and total recruitment (M, including H₁ and renesting), if combined with data more specific to a local area, would guide management aimed at affecting multiple life history stages whose relative importance will vary across the landscape.     

Spatial Simulation of Epizootics Caused by Beauveria bassiana in Russian Wheat Aphid Populations

Models of disease dynamics commonly make the assumption of spatial homogeneity in the underlying host population. However, insect behavior may result in spatially heterogeneous populations with which pathogens interact. We modified a simulation model of temporal and spatial population dynamics of the Russian wheat aphid, Diuraphis noxia, on preferred or nonpreferred host plants, by incorporating effects of the entomopathogenic fungus, Beauveria bassiana. Epizootic parameters included time from inoculation of aphids until death, duration of sporulation, and estimated exposure probability. Simulations first predicted results of previously described experiments in which D. noxia adults were inoculated with conidial suspensions or water and placed on wheat or oat seedlings in 81-plant grids in cages. Subsequently, large-scale simulations were run for hypothetical field situations on 50 × 50-plant grids of wheat or oat. With B. bassiana present for both cage and larger scale simulations, results indicated that, on oat, an expanding infection front lagged behind the expanding aphid population front. Continual aphid movement from hosts resulted in many escapes, and the aphid population persisted at slightly reduced levels. On the preferred wheat host, patterns developed with pockets of infected aphids and other pockets of healthy aphids. Localized aphid populations that escaped initial infestation were able to proliferate, whereas other local populations were greatly reduced or became extinct due to lack of movement from the hosts, resulting in increased exposure to pathogen inoculum. Thus, proliferation and fluctuation of the pathogen were strongly influenced by the plant hosts' effects on aphid movement behavior. Incorporating spatial dynamics into disease models should prove useful in other efforts to predict biological control efficacy by entomopathogenic fungi in heterogeneous habitats.     

Modelling the epidemiology of hepatitis B in New Zealand

Hepatitis B is a vaccine preventable disease caused by the hepatitis B virus (HBV) that can induce potentially fatal liver damage. It has the second highest mortality rate of all vaccine preventable diseases in New Zealand. Vaccination against HBV was introduced in New Zealand in 1988, and the country is now categorised with overall low endemicity but with areas of both high and medium endemic levels. We present an SECIR compartmental mathematical model, with the population divided into age classes, for the transmission of HBV using local data on incidence of infection and vaccination coverage. We estimate the basic reproduction number, R₀, to be 1.53, and show that the vaccination campaign has substantially reduced this below one. However, a large number of carriers remain in the population acting as a source of infection.     

A checkpoint-oriented cell cycle simulation model

Modeling and in silico simulations are of major conceptual and applicative interest in studying the cell cycle and proliferation in eukaryotic cells. In this paper, we present a cell cycle checkpoint-oriented simulator that uses agent-based simulation modeling to reproduce the dynamics of a cancer cell population in exponential growth. Our in silico simulations were successfully validated by experimental in vitro supporting data obtained with HCT116 colon cancer cells. We demonstrated that this model can simulate cell confluence and the associated elongation of the G1 phase. Using nocodazole to synchronize cancer cells at mitosis, we confirmed the model predictivity and provided evidence of an additional and unexpected effect of nocodazole on the overall cell cycle progression. We anticipate that this cell cycle simulator will be a potential source of new insights and research perspectives.     

Extinction of marine renewable resources: a demographic analysis

A simple (deterministic) population dynamics model is used to examine the level of fishing mortality at which a population is expected to be driven to extinction (F _crash). Values for F _crash are determined for six marine fish species (Cape hake, blue grenadier, blue warehou, school shark, gummy shark, and orange roughy) subject to commercial harvest. The sensitivity of the value of F _crash to changing the selectivity pattern of the fishery and the relationship between the size of the reproductive component of the population and subsequent births to allow for depensatory effects is examined. F _crash is greatest for highly productive species and when the fishery does not target immature animals. The ratio of F _crash to the fishing mortality at which maximum sustainable yield is achieved, F _MSY, is a decreasing function of the productivity of the population. The possibility of depensation has little impact on F _MSY but can substantially reduce the ratio F _crash/F _MSY. A series of stochastic simulations is conducted to assess the probability of detecting that the extent of fishing exceeds F _crash using the current IUCN A criterion. The results of these simulations are also used to determine the probability that the IUCN A criteria will be triggered when fishing takes place at F _MSY. The results indicate that there are substantial probabilities of incorrectly identifying species being harvested at F _MSY as being threatened during the 'fishing down' phase and also of not identifying species actually at risk of extinction if fishing mortality is not reduced. Received: January 14, 1999 / Accepted: April 27, 1999     

Toxoplasma gondii: uptake and survival of oocysts in free-living amoebae

Waterborne transmission of the oocyst stage of Toxoplasma gondii can cause outbreaks of clinical toxoplasmosis in humans and infection of marine mammals. In water-related environments and soil, free-living amoebae are considered potential carriers of various pathogens, but knowledge on interactions with parasitic protozoa remains elusive. In the present study, we assessed whether the free-living Acanthamoebacastellanii, due to its phagocytic activity, can interact with T. gondii oocysts. We report that amoebae can internalize T. gondii oocysts by active uptake. Intracellular oocysts in amoebae rarely underwent phagocytic lysis, retained viability and established infection in mice. Interaction of T. gondii with amoebae did not reduce the infectivity and pathogenicity of oocysts even after prolonged co-cultivation. Our results show that uptake of oocysts by A. castellanii does not restrain the transmission of T. gondii in a murine infection model.     

Montanide™ ISA 71 VG adjuvant enhances antibody and cell-mediated immune responses to profilin subunit antigen vaccination and promotes protection against Eimeria acervulina and Eimeria tenella

The present study was conducted to investigate the immunoenhancing effects of Montanide™ ISA 71 VG adjuvant on profilin subunit antigen vaccination. Broiler chickens were immunized subcutaneously with a purified Eimeria acervulina recombinant profilin protein, either alone or mixed with ISA 71 VG, and host immune responses were evaluated. After secondary immunization, antigen-specific antibody and T-cell responses were higher in the group which received profilin plus ISA 71 VG compared with the other groups. Furthermore, body weight gains and fecal oocyst shedding were evaluated following oral challenge infection with live E. acervulina or Eimeria tenella oocysts. Vaccination with profilin plus ISA 71 VG reduced oocyst shedding compared with animals immunized with profilin alone. These results demonstrate that the recombinant profilin subunit vaccine, when given in combination with Montanide™ ISA 71 VG, augments protective immunity against E. acervulina and E. tenella.