Disgust as an emotional driver of vaccine attitudes and uptake? A mediation analysis.

Research on the drivers of vaccine acceptance has expanded but most interventions fall short of coverage targets. We explored whether vaccine uptake is driven directly or indirectly by disgust with attitudes towards vaccines acting as a possible mediator. An online cross-sectional study of 1007 adults of the USA via Amazon's Mechanical Turk was conducted in January 2017. The questionnaire consisted of four sections: (1) items assessing attitudes towards vaccines and vaccine uptake, (2) revised Disgust Scale (DS-R) to measure Disgust Sensitivity, (3) Perceived Vulnerability to Disease scale (PVD) to measure Germ Aversion and Perceived Susceptibility, and (4) socio-demographic information. Using mediation analysis, we assess the direct, the indirect (through Vaccine Attitudes) and the total effect of Disgust Sensitivity, Germ Aversion and Perceived Susceptibility on 2016 self-reported flu vaccine uptake. Mediation analysis showed the effect of Disgust Sensitivity and Germ Aversion on vaccine uptake to be twofold: a direct positive effect on vaccine uptake and an indirect negative effect through Vaccine Attitudes. In contrast, Perceived Susceptibility was found to have only a direct positive effect on vaccine uptake. Nonetheless, these effects were attenuated and small compared to economic, logistic and psychological determinants of vaccine uptake.

On the origin and timing of Zika virus introduction in Brazil.

The timing and origin of Zika virus (ZIKV) introduction in Brazil has been the subject of controversy. Initially, it was assumed that the virus was introduced during the FIFA World Cup in June-July 2014. Then, it was speculated that ZIKV may have been introduced by athletes from French Polynesia (FP) who competed in a canoe race in Rio de Janeiro in August 2014. We attempted to apply mathematical models to determine the most likely time window of ZIKV introduction in Brazil. Given that the timing and origin of ZIKV introduction in Brazil may be a politically sensitive issue, its determination (or the provision of a plausible hypothesis) may help to prevent undeserved blame. We used a simple mathematical model to estimate the force of infection and the corresponding individual probability of being infected with ZIKV in FP. Taking into account the air travel volume from FP to Brazil between October 2013 and March 2014, we estimated the expected number of infected travellers arriving at Brazilian airports during that period. During the period between December 2013 and February 2014, 51 individuals travelled from FP airports to 11 Brazilian cities. Basing on the calculated force of ZIKV infection (the per capita rate of new infections per time unit) and risk of infection (probability of at least one new infection), we estimated that 18 (95% CI 12-22) individuals who arrived in seven of the evaluated cities were infected. When basic ZIKV reproduction numbers greater than one were assumed in the seven evaluated cities, ZIKV could have been introduced in any one of the cities. Based on the force of infection in FP, basic reproduction ZIKV number in selected Brazilian cities, and estimated travel volume, we concluded that ZIKV was most likely introduced and established in Brazil by infected travellers arriving from FP in the period between October 2013 and March 2014, which was prior to the two aforementioned sporting events.

Positive selection drives accelerated evolution of mosquito salivary genes associated with blood-feeding.

The saliva of bloodsucking animals contains dozens to hundreds of proteins that counteract their hosts' haemostasis, inflammation and immunity. It was previously observed that salivary proteins involved in haematophagy are much more divergent in their primary sequence than those of housekeeping function, when comparisons were made between closely related organisms. While this pattern of evolution could result from relaxed selection or drift, it could alternatively be the result of positive selection driven by the intense pressure of the host immune system. We investigated the polymorphism of five different genes associated with blood-feeding in the mosquito Anopheles gambiae and obtained evidence in four genes for sites with signatures of positive selection. These results add salivary gland genes from bloodsucking arthropods to the small list of genes driven by positive selection.

Global pharmacogenomics: Impact of population diversity on the distribution of polymorphisms in the CYP2C cluster among Brazilians.

The impact of biogeographical ancestry, self-reported 'race/color' and geographical origin on the frequency distribution of 10 CYP2C functional polymorphisms (CYP2C8*2, *3, *4, CYP2C9*2, *3, *5, *11, CYP2C19*2, *3 and *17) and their haplotypes was assessed in a representative cohort of the Brazilian population (n=1034). TaqMan assays were used for allele discrimination at each CYP2C locus investigated. Individual proportions of European, African and Amerindian biogeographical ancestry were estimated using a panel of insertion-deletion polymorphisms. Multinomial log-linear models were applied to infer the statistical association between the CYP2C alleles and haplotypes (response variables), and biogeographical ancestry, self-reported Color and geographical origin (explanatory variables). The results showed that CYP2C19*3, CYP2C9*5 and CYP2C9*11 were rare alleles (<1%), the frequency of other variants ranged from 3.4% (CYP2C8*4) to 17.3% (CYP2C19*17). Two distinct haplotype blocks were identified: block 1 consists of three single nucleotide polymorphisms (SNPs) (CYP2C19*17, CYP2C19*2 and CYP2C9*2) and block 2 of six SNPs (CYP2C9*11, CYP2C9*3, CYP2C9*5, CYP2C8*2, CYP2C8*4 and CYP2C8*3). Diplotype analysis generated 41 haplotypes, of which eight had frequencies greater than 1% and together accounted for 96.4% of the overall genetic diversity. The distribution of CYP2C8 and CYP2C9 (but not CYP2C19) alleles, and of CYP2C haplotypes was significantly associated with self-reported Color and with the individual proportions of European and African genetic ancestry, irrespective of Color self-identification. The individual odds of having alleles CYP2C8*2, CYP2C8*3, CYP2C9*2 and CYP2C9*3, and haplotypes including these alleles, varied continuously as the proportion of European ancestry increased. Collectively, these data strongly suggest that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies of the CYP2C cluster in order to avoid spurious conclusions based on improper matching of study cohorts. This conclusion extends to other polymorphic pharmacogenes among Brazilians, and most likely to other admixed populations of the Americas.

Effectiveness of BCG vaccination among leprosy contacts: a cohort study.

The study assessed the effectiveness of BCG vaccination against leprosy among the contacts of 1161 leprosy patients at the FIOCRUZ Leprosy Outpatient Clinic, RJ, Brazil, from June 1987 to December 2006. Following National Leprosy Program guidelines, the clinic has administered one-to-two doses to all healthy contacts since 1991. Among the 5680 contacts, 304 (5.4%) already had leprosy. Of the 5376 eligible healthy contacts, 3536 were vaccinated, 30 of whom were excluded due to previous or current tuberculosis, or HIV. In 18 years of follow up, 122 (2.15%) incident cases were diagnosed (58 vaccinated and 64 not), 28 occurring in the first year of follow up (21 vaccinated, 16 with no scar). The protection conferred by BCG was 56% and was not substantially affected by previous BCG vaccination (50% with a scar and 59% without). The risk of tuberculoid leprosy during the initial months was high among those vaccinated with no scar. However, it had substantially declined by the first year and in the following years, when the protection rate in this group reached 80%. Since Brazil is endemic for leprosy and the detection rate is not declining satisfactorily, vaccinating all contacts could be an effective means of substantially reducing the incidence of leprosy.

A new model for the population pharmacokinetics of didanosine in healthy subjects.

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0%, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2%, respectively. The relatively high (>30%) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

The impact of imperfect vaccines on the evolution of HIV virulence.

A theoretical framework is proposed on which some hypotheses related to the impact of imperfect vaccines on the evolution of HIV virulence can be tested. For this, a linear increase of risk behaviour with vaccine efficacy is assumed. This is based on the hypothesis that people are prone to relax preventive measures by knowing that they and their partners are vaccinated and that this effect is more intense the more effective the vaccine is known to be. An additional, and perhaps more important hypothesis is related to the theoretical possibility that increased risk behaviour of some vaccinated individuals in partially protected populations could act as a selective pressure toward more virulent HIV strains. Those hypotheses were tested by a mathematical model that considers three different HIV strains competing against each other in a population partially protected by imperfect vaccines of distinct efficacies. Simulations of the model demonstrated that, under the above hypotheses, there is a shift in HIV virulence towards more aggressive strains with increase in vaccine efficacy, associated with a marked reduction in the total amount of transmission and, consequently, in the prevalence of HIV. Potential ways for further testing the theory/model and the implications of the results are discussed.

Protease inhibitors as initial therapy for individuals with an intermediate risk of HIV disease progression: is more necessarily better?

OBJECTIVE: To compare three possible therapeutic strategies for the treatment of patients with an intermediate risk of HIV disease progression. DESIGN: Mathematical modeling based on assumptions derived from published data. METHODS: A parametric survival model was fitted to empirical data to describe the survival trajectory of untreated individuals. It was assumed that successful treatment decreases the risk of disease progression curing the first year after its introduction by a constant that is dependent on the magnitude of the initial drop in HIV viral load. Thereafter, individual members of the treatment cohort follow different pathways, depending on the duration of the initial response or, in case of virologic failure, the response to a new drug regimen. RESULTS: Sub-groups of patients starting therapy with two nucleoside reverse transcriptase inhibitors (NRTI) or two NRTI and a protease inhibitor had the highest instantaneous risk of disease progression at the end of the 5-year follow-up period. Patients who started therapy with two NRTI and a non-NRTI had the lowest likelihood of progression to AIDS or death at 5 years of follow-up. This is because, in the case of the subgroup whose initial treatment included a protease inhibitor, failure rates due to non-adherence to therapy are high and response to salvage therapy is limited by past protease inhibitor experience. CONCLUSIONS: Despite the superior virologic potency of the protease inhibitor-containing regimens, in this analysis other strategies performed equally well or even better. In the absence of solid empirical data and until the advent of antiretroviral regimens that are shown to be safe, simple to take, and maximally suppress viral load, caution may be required in selecting the long-term therapy for patients with less advanced HIV disease.

Vaccine-associated paralytic poliomyelitis: a retrospective cohort study of acute flaccid paralyses in Brazil.

BACKGROUND: At the present time, in Brazil and other countries in the Americas, the only cases of paralytic poliomyelitis due to poliovirus are caused by vaccine strains. The recognition of possible determinants of vaccine-associated paralytic poliomyelitis (VAPP) by public health surveillance and immunization programmes is relevant to inform the debate on criteria for case definition and vaccination strategies. METHODS: A retrospective cohort study based on the cases of acute flaccid paralysis (AFP) reported to the Ministry of Health (MoH) was designed, with the objective of studying cases of VAPP in Brazil between 1989 and 1995. Clinical, laboratory and epidemiological data from 3656 acute flaccid paralysis (AFP) cases, 30 of them diagnosed as VAPP, were analysed. RESULTS: An 8.88 risk ratio of VAPP (95% CI : 4.37-18.03) was found when comparing individuals who received oral poliovirus vaccine (OPV) between 4 and 40 days before the onset of paralysis and individuals who did not receive the vaccine within this period. A risk of 1 case/2.39 million first doses and 1 case/13.03 million OPV doses administered was estimated for the general population. CONCLUSIONS: Cases of AFP who received OPV between 4 and 40 days before the onset of paralysis and had fever, a prodrome of gastrointestinal symptoms, history of first dose of OPV, isolation of vaccine poliovirus type 2, and young age deserve careful investigation, since they are at increased risk for the condition studied.

The behaviour of common measures of association used to assess a vaccination programme under complex disease transmission patterns--a computer simulation study of malaria vaccines.

Case-control studies have been evoked as important alternatives to randomized clinical trials in the evaluation of infectious disease interventions. Using computer simulations, we compare the behaviour of common measures of association derived from case-control studies in the context of a malaria vaccine programme administered under complex transmission conditions. Several simplifying assumptions of previous workers have been relaxed and the simulated conditions are endemic rather than epidemic. The common estimators of association used in case-control studies remain unbiased only in limited circumstances. The term dependent happenings, first defined by Ross in 1916, is resurrected. Since the number of people becoming infected is dependent on the number of people already infected, control programmes in infectious diseases produce direct as well as indirect effects. Three different study designs with different pairs of comparison populations are defined. The choice of comparison population can be used to differentiate direct from indirect effects. In order to clarify the direct effects of a vaccination programme the comparison groups must be subjected to identical transmission intensities. In contrast, the referent group must remain unaffected by consequences of the intervention to determine indirect effects.

Assessment of the direct effectiveness of BC meningococcal vaccine in Rio de Janeiro, Brazil: a case-control study.

BACKGROUND: Meningococcal disease is still a serious public health problem in many countries. A vaccine produced by Cuba was the first product against B meningococcus available on a large scale. In an attempt to control the increasing incidence of this serogroup in greater Rio de Janeiro, Brazil, the vaccine was used in 1990 in children aged 6 months-9 years. About 1.6 million children were vaccinated. METHODS: In order to assess the direct effectiveness of the vaccine in preventing disease, we conducted a case-control study during the first year after vaccination. Using a hospital-based census, we selected all children hospitalized with meningococcal disease and sampled the control group among children hospitalized with other types of meningitis. Vaccine effectiveness was estimated from the relationship, 1-OR, where OR (odds ratio) was the exponential of the logistic regression coefficient for the association between meningococcal disease and previous vaccination. RESULTS: A total of 275 cases and 279 controls were selected between September 1990 and October 1991. The summary adjusted measure of protection against serogroup B was 54% (95% confidence interval [CI]: 20-74%). Estimated protection varied among different age strata and place of residence, being high among children aged > or = 4 years, 71% (95% CI: 34-87%), and among those who lived in the City of Rio de Janeiro, 74% (95% CI: 42-89%). CONCLUSIONS: The results suggest that the vaccine produced by Cuba may offer protection against serogroup B meningococcal disease, but its effects may not be homogeneous.

PIP: Meningococcal disease is still a serious public health problem in many countries. A vaccine produced by Cuba was the first product against B meningococcus available on a large scale. In an attempt to control the increasing incidence of this serogroup in greater Rio de Janeiro, Brazil, the vaccine was used in 1990 in children 6 months-9 years old. About 1.6 million children were vaccinated. In order to assess the direct effectiveness of the vaccine in preventing disease, a case-control study was conducted during the first year after vaccination. Using a hospital-based census, all children hospitalized with meningococcal disease caused by Neisseria meningitidis were selected, and the control group came from children hospitalized with other types of meningitis at the Sao Sebastiao State Infectology Institute. Vaccine effectiveness was estimated, using ordinary logistic regression, from the relationship, 1 - OR, where OR (odds ratio) was the exponential of the logistic regression coefficient for the association between meningococcal disease and previous vaccination. A total of 275 cases and 279 controls were selected between September 1990 and October 1991. 57% of the total cases belonged to serogroup B and 7% to serogroup C. The case fatality rate was 11%. Of the 279 controls, 46% were related to viral meningitis, 34% were related to meningitis caused by bacteria other than N. meningitidis, 13% were related to postmumps meningitis, 5% to tuberculosis meningitis, and 2% to other diseases. The summary-adjusted measure of protection against serogroup B was 54% (95% confidence interval [CI]: 20-74%). The combined vaccine effectiveness for 230 cases and 232 controls amounted to 58% (95% CI: 31-74%). Estimated protection varied among different age strata and place of residence, being high among children or= 4 years old, 71% (95% CI: 34-87%), and among those who lived in the City of Rio de Janeiro, 74%, (95% CI: 42-89%). The results suggest that the vaccine produced by Cuba may offer protection against serogroup B meningococcal disease, but its effects may not be homogeneous.

Hepatitis A incidence rate estimates from a pilot seroprevalence survey in Rio de Janeiro, Brazil.

BACKGROUND: To assess the impact of water sanitation and sewage disposal, part of a major environmental control programme in Rio de Janeiro, we carried out sero-prevalence studies for Hepatitis A virus (HAV) in three micro-regions in Rio de Janeiro. Each region varied with regard to level of sanitation. We are interested in assessing the discriminating power of age-specific prevalence curves for HAV as a proxy for improvement in sanitation. These curves will serve as baseline information to future planned surveys as the sanitation programme progresses. METHODS: Incidence rate curves from prevalence data are estimated parametrically via a Weibull-like survival function, and non-parametrically via maximum likelihood and monotonic splines. Sera collected from children and adults in the three areas are used to detect antibodies against HAV through ELISA. RESULTS: We compare baseline incidence curves at the three sites estimated by the three methods. We observe a strong negative correlation between level of sanitation and incidence rates for HAV infection. Incidence estimates yielded by the parametric and non-parametric approaches tend to agree at early ages in the microregion showing the best level of sanitation and to increasingly disagree in the other two. CONCLUSION: Our results support the choice of HAV as a sentinel disease that is associated with level of sanitation. We also introduce monotonic splines as a novel non-parametric approach to estimate incidence from prevalence data. This approach outperforms current estimating procedures.

Evaluation of SPf66 malaria vaccine efficacy in Brazil.

This paper reports the efficacy results of the randomized, placebo-controlled, field trial of SPf66 malaria vaccine in Costa Marques, Rondonia, Brazil. This region is characterized by the seasonal distribution of Plasmodium falciparum and P. vivax infections, and the recent occupation by migrants from nonendemic areas. A total of 800 individuals of both sexes, ranging in age from seven to 60 years, were included in the study. Of the initial cohort, 572 participants completed the vaccination schedule. Clinical and parasitologic evaluations were obtained by active and passive searches on a periodic basis. The overall protective efficacy against P. falciparum infections was -1.6% (-32.9% to 22.4%), and 14.1% (-17.0% to 36.9%) for the first episode. The overall protective efficacy for P. vivax infections was -19.7% (-44.8% to 1.03%), and -10.8% (-41.1% to 12.8%) for the first episode. No statistical evidence of an overall significant protective effect of SPf66 malaria vaccine against P. falciparum and P. vivax malaria was obtained in this trial.

PIP: The efficacy of the SPf66 malaria vaccine was evaluated in a randomized, placebo-controlled, field trial in Costa Marques, Rondonia, Brazil; a region characterized by seasonal Plasmodium falciparum and P. vivax infections and a recent influx of migrants from nonendemic areas. This vaccine is composed of sequences of 3 peptides from P. falciparum merozoite, erythrocytic stages, and a peptide from the circumsporozoite protein. Enrolled were 800 predominantly migrant men and women, 7-60 years of age, 572 of whom completed the vaccination schedule. Clinical and parasitologic evaluations were obtained by periodic active and passive searches up to Day 720. After the third dose, 5684 blood samples were collected and 967 (520 in the vaccine group and 447 in the placebo group) were positive. 212 P. falciparum infections (107 episodes in 76 participants in the vaccine group and 105 in 85 members of the placebo group) were confirmed after exclusion of relapses and treatment failures. A total of 427 P. vivax infections were detected (233 in 138 participants in the vaccine group and 194 in 127 participants in the placebo group). The overall protective efficacy against P. falciparum infections was -1.6% (95% confidence interval (CI), -32.9-22.4%) and 14.1% (95% CI, -17.0-36.9%) for the first episode. The overall protective efficacy for P. vivax infections was -19.7% (95% CI, -44.8-1.03%) and -10.8% (95% CI, -41.1-12.8%) for the first episode. These findings fail to provide evidence of an overall significant protective effect of the SPf66 malaria vaccine in this population.

Risk assessment of yellow fever urbanization in Rio de Janeiro, Brazil.

Yellow fever (YF), an arthropod-borne viral disease, occurs in regions of tropical America and Africa. Sylvatic YF is endemic in the north and west of Brazil. Urban YF, on the other hand, has not been reported in the country since 1942. However, the widespread presence of the YF urban vector in Brazil has lead to concern about the potential re-emergence of YF in urban centres. Here, we assess the risk of YF emergence in the city of Rio de Janeiro, Brazil, by estimating the probability of infected individuals arriving from YF-endemic areas, and the probability of infective individuals triggering an epidemic. We found that the risk of urban YF emergence may reach values as high as 29% during the epizootic periods but the precision of the estimate is low.

Detection of antibodies against hepatitis A virus in eluates of blood spotted on filter-paper: a pilot study in Rio de Janeiro, Brazil.

The validity of blood spotted on to filter-paper (BSOFP) eluates for the detection of antibodies against hepatitis A virus (HAV) was investigated in 718 individuals (children and adults) during a field study in a small area in Rio de Janeiro State, Brazil. Serum samples were considered the 'gold standard'. BSOFP eluates were analyzed by 2 different techniques: microplate competitive enzyme-linked immunosorbent assay (ELISA) of the whole study group and microparticle enzyme immune assay (MEIA) of a subsample of 59 individuals. For BSOFP eluates by ELISA, sensitivity and specificity were 89.6% (95% CI: 84.7-93.1) and 97.5% (95% CI: 95.6-98.7), respectively. For a seroprevalence of anti-HAV antibodies of 32%, the positive predictive value was 94.5% (95% CI: 90.3-97.0) and the negative predictive value was 95.2% (95% CI: 92.8-96.8). The test efficiency was 95.0% (95% CI: 93.1-96.4). Similar results were found for BSOFP eluates by MEIA. Agreement between the 2 techniques used for BSOFP (ELISA and MEIA) was also high (kappa = 0.93). These results encourage the more widespread application of BSOFP as a means of surveillance for large-scale epidemiological studies for hepatitis A.

Carbamazepine: a bioequivalence study and limited sampling modeling.

OBJECTIVES: To assess the bioequivalence of 2 formulations of carbamazepine and to develop and validate limited sampling strategy (LSS) models for estimating the area under the plasma concentration-time curve (AUC0-infinity) and the peak plasma concentration (Cmax) of carbamazepine. METHODS: Twenty-four (12 men, 12 women) healthy volunteers received single oral doses (400 mg) of carbamazepine, as reference and test conventional-release formulations, in a standard 2-sequence, 2-period crossover design. Bioequivalence assessment was based on the individual ratios of log-transformed values of AUC0-infinity and Cmax LSS modeling was developed in a training set of 12 randomly assigned volunteers and was validated on the other 12 subjects (validation set). RESULTS: Carbamazepine AUC0-infinity and Cmax can be accurately predicted (R2 = 0.89 - 0.95, precision = 2.6 - 7.2%) by single-point (72 h) and 2-point LSS models (6, 32 h), respectively. Bioequivalence assessments based on LSS-derived AUC0-infinity and Cmax provided results similar to those obtained using all the concentration-in-plasma data points, and indicated that the 2 formulations are bioequivalent. CONCLUSION: One-and 2-point LSS models provided accurate estimates of carbamazepine's AUC0-infinity and Cmax, and allowed correct assessment of bioequivalence between the formulations studied.

Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone.

Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration (Cmax) of 4-methylaminoantipyrine (MAA), an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336), measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC(0-infinity) and the Cmax of MAA can be accurately predicted (R2>0.95, bias <1.5%, precision between 3.1 and 8.3%) by LSS models based on two sampling times. Validation tests indicate that the most informative 2-point LSS models developed for one formulation provide good estimates (R2>0.85) of the AUC(0-infinity) or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h), but using different coefficients for AUC(0-infinity) and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R2>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4%) as well as for plasma concentration data sets generated by simulation (R2>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%). Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC(0-infinity) and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boosting.

Population effects of malaria vaccination programs will depend on the stage specificity of the vaccine, its duration of effectiveness, whether it is responsive to natural boosting, the proportion vaccinated, and the preexisting endemic conditions. This paper develops models of infection-blocking (sporozoite), disease-modifying (merozoite), and transmission-blocking (gametic) vaccines. It explores numerically their different effects on prevalence of infection and disease when utilized in different types of immunization programs at various levels of coverage. Simulations show that possible qualitative consequences of malaria vaccination programs include decreased prevalence of infection and disease and decreased prevalence of infection without a corresponding decrease in prevalence of disease. Epidemics, either one-time or cyclical, could occur. These effects could be accompanied by changes in the age distribution of disease. Finally, vaccination could contribute to elimination of transmission. The duration of effectiveness of the malaria vaccine relative to the duration of natural immunity could have important consequences for the unvaccinated. The problem of predicting a threshold for elimination of transmission is discussed.

Modeling malaria vaccines. I: New uses for old ideas.

Starting from a modification of the model of malaria transmission developed for the Garki project, this paper develops a model containing variables relevant to the stimulation of malaria vaccination programs. Modifications include (1) integration of maintenance of immunity dependent on boosting and the possibility of loss of immunity; (2) introduction of a boosting factor distinct from susceptibility to infection; (3) reinterpretation of the epidemiological compartments of positive immunes and nonimmunes in terms of severity of disease rather than just infection; (4) interpretation of the different stage-specific levels of immunity; (5) discrimination between different susceptibilities for the immune and nonimmune classes; (6) reformulation of the expression for acquisition of immunity to be biologically more acceptable. Simulations using the Garki model, Nedelman's modification of it, and our Basic model compare the similarities and differences in the predictive behavior of the models. Simulations using the Basic model reproduce observed periodic fluctuations of malaria attributed to the interplay of transmission-blocking immunity and loss of immunity in the absence of boosting in areas of unstable malaria transmission.

Epidemiologic effects of vaccines with complex direct effects in an age-structured population.

Vaccines can alter the dynamic interaction of an infectious agent with a host in complex ways. The effect of routine childhood immunization on age-specific cases was studied in an age-structured population, assuming different vaccine effects at the individual level. Assumptions about vaccine efficacy include partial protection to infection and disease, reduction in infectiousness, waning of protection, and boosting of the level and duration of protection by natural infection. The concept of relative pathogenicity is introduced to describe the effect of a vaccine on the development of disease conditional on being infected. The concepts of the immunologically naive susceptible, naive susceptible equivalent, and relative residual infection potential are introduced in the context of defining the reproduction number of a population vaccinated with a partially protective vaccine. Sensitivity to boosting has a particularly pronounced effect in reducing the number of older vaccinated cases. Near the threshold for eliminating transmission, the dynamic behavior and number as well as age distribution of cases is very sensitive to the degree of protection and relative residual infectiousness. The number of unvaccinated cases is more sensitive to the level of coverage than to the type of vaccine, while the number of vaccinated cases is very sensitive to assumptions about vaccine efficacy.