Predicting residual immunity against smallpox.
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Antibodies, Viral↗
Biomedical subjects
Martin Eichner
Publications and source records attributed to Martin Eichner.
The earliest notes on the reproduction number in relation to herd immunity: Theophil Lotz and smallpox vaccination.
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Epidemiology↗
Still protected against smallpox? Estimation of the duration of vaccine-induced immunity against smallpox.
BACKGROUND: Although the potential for bioterrorism has led to discussions on the durability of vaccine-induced immunity, the actual duration of protection against smallpox is still unknown. It has previously been suggested that at least partial protection against severe and fatal smallpox may persist throughout life. METHODS: In this article, we analyzed 6 major smallpox outbreaks that occurred before and after 1900 in the United Kingdom. These analyses are based on the age-dependent incidence of smallpox and the fraction of severe manifestations among individuals with or without prior vaccination. We used a likelihood-based approach to estimate the duration of immunity from the age-specific frequencies. RESULTS: The expected median duration of protection from disease ranged from 11.7 to 28.4 years after primary vaccination, and the qualitative pattern of duration could be described using Gompertz's Law. Vaccinated individuals appear to have been protected from severe disease with more than 50% probability even 50 years after successful primary vaccination. CONCLUSIONS: These findings suggest that successful primary vaccination offered full protection for a few decades, with partial protection from severe smallpox possibly lasting a lifetime, for a substantial fraction of the population.
Age Factors↗
Transmission potential of primary pneumonic plague: time inhomogeneous evaluation based on historical documents of the transmission network.
BACKGROUND: The transmission potential of primary pneumonic plague, caused by Yersinia pestis, is one of the key epidemiological determinants of a potential biological weapon, and requires clarification and time dependent interpretation. METHOD: This study estimated the reproduction number and its time dependent change through investigations of outbreaks in Mukden, China (1946), and Madagascar (1957). Reconstruction of an epidemic tree, which shows who infected whom, from the observed dates of onset was performed using the serial interval. Furthermore, a likelihood based approach was used for the time inhomogeneous evaluation of the outbreaks for which there was scarcity of cases. RESULTS: According to the estimates, the basic reproduction number, R(0), was on the order of 2.8 to 3.5, which is higher than previous estimates. The lower 95% confidence intervals of R(0) exceeded unity. The effective reproduction number declined below unity after control measures were introduced in Mukden, and before the official implementation in Madagascar. CONCLUSION: While the time course of the latter outbreak could be explained by intrinsic factors and stochasticity in this remote and scarcely populated area, the former in Mukden suggests the possible continued chains of transmission in highly populated areas. Using the proposed methods, the who infected whom information permitted the evaluation of the time inhomogeneous transmission potential in relation to public health measures. The study also tackles the problem of statistical estimation of R(0) based on similar information, which was previously performed simply by counting the number of secondary transmissions regardless of time.
China↗
Diminished response to interleukin-10 and reduced antibody-dependent cellular cytotoxicity of cord blood monocyte-derived macrophages.
Monocyte-derived macrophage (MPhi) subsets are generated by antagonistic induction pathways. A helper MPhi-type (Mh-MPhi) is induced by interferon gamma (IFN-gamma), whereas a cytotoxic MPhi-type (Mc-MPhi), induced by interleukin-10 (IL-10), is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Compared with MPhi from healthy adults [peripheral blood monocyte-derived macrophages (PBMPhi)], cord blood MPhi (CBMPhi) were found less capable of generating Mh-MPhi. Here we tested the hypothesis that their generation of Mc-MPhi via IL-10 is also impaired. MPhi surface markers were phenotyped. IL-10 protein and mRNA production were detected after stimulation [alphaCD3 monoclonal antibody (mAb)]. CBMPhi or PBMPhi were co-cultured with MPhi-depleted mononuclear cells of adults and CD4-targeting antibodies as models for ADCC were added. In cord blood, we found diminished alphaCD3-induced IL-10 protein and mRNA production (p < 0.05 versus adults). Basal CD16 and HLA-DR expressions on CBMPhi of preterm and full-term neonates were lower (p < 0.05 versus PBMPhi). IL-10 had reduced effects on CD16 up- and HLA-DR down-modulation on CBMPhi (p < 0.05 versus PBMPhi). CD4-directed receptor modulation and deletion were reduced in the presence of CBMPhi (p < 0.05 versus PBMPhi). IL-10 failed to enhance their ADCC capacity, which was in contrast to PBMPhi (p < 0.05). These data suggest that CBMPhi have an impaired cytotoxic capacity via lower sensitivity toward IL-10.
Antibodies, Monoclonal↗
Effect of dexamethasone on B7 regulation and T cell activation in neonates and adults.
The safety of dexamethasone for neonates has been questioned, partly because of its multiple unspecific effects on the immune system. Specific effects of dexamethasone on co-stimulatory and immune suppressive functions of neonatal compared with adult macrophages (MPhi) are not known. We evaluated the effect of dexamethasone on the expression and regulation of MPhi B7 family receptors (B7-1, CD80; B7-2, CD86) and on their ability to co-stimulate T cells. Cord blood macrophages (CBMPhi) and MPhi from healthy adults (PBMPhi) were isolated, and cell surface markers were phenotyped by flow cytometry. In tissue culture, cells were exposed to dexamethasone, interferon-gamma (IFN-gamma), cAMP, or a T cell mitogen (alphaCD3) and examined for their capacity to activate or destroy T cells. CBMPhi were less able to up-regulate CD80 and CD86 than PBMPhi (p < 0.05). Dexamethasone inhibited the up-regulation of CD80, CD86, and HLA-DR on PBMPhi and even more so on CBMPhi (p < 0.05 versus PBMPhi for CD80 and CD86). In the presence of dexamethasone, stimulation with alphaCD3 MAb enhanced cytotoxic functions of PMBMPhi and CB(mu)phi with an increase in deleted T cells, a reduced fraction of enlarged T cells, and an inhibition of T cell CD28 up-regulation, which again were more pronounced with CBMPhi (p < 0.05 versus PBMPhi). In conclusion, neonatal MPhi are exquisitely sensitive to the inhibitory effects of dexamethasone on B7 expression. Although perhaps producing the desired therapeutic effect, dexamethasone may do so in newborns at the expense of a near complete paralysis of MPhi-dependent T cell function.
Adult↗
Determinants of the eradicability of filarial infections: a conceptual approach.
Lymphatic filariasis and onchocerciasis are subject to major intervention programs by the WHO. The Onchocerciasis Control Programme in West Africa was launched 30 years ago and has led to considerable insights into the control of this infection. The Global Alliance to Eliminate Lymphatic Filariasis is a relatively recent control program with ambitious targets concerning its efficacy and its schedule. These expectations, however, are based on certain assumptions about the density-dependent processes of limitation and facilitation which determine eradicability: the levels of transmission thresholds and breakpoints. Here, we review these processes operating in filarial infections and show their impact on the persistence of the parasite, as well as pointing out those issues where more information is required to develop sound predictions about the eradicability of these infections.
Animals↗
Effects of intraoperative blood salvage on leukocyte recruitment to the endothelium.
BACKGROUND: The contamination of salvaged wound blood with activated leukocytes has been suspected to play a role in leukocyte-mediated tissue injury by increased adhesion to the endothelium. To verify this hypothesis, the authors performed a clinical study to examine the effects of blood salvage on leukocyte-endothelial interactions. METHODS: Expression of L-selectin, CD18, and CD11b and leukocyte adhesion to activated endothelium from human umbilical veins were measured in 25 patients undergoing major orthopedic surgery. Adhesion of fluorescently labeled leukocytes was examined in a flow chamber at shear rates of 50-1,600 s. Comparisons were made between samples from venous blood and from processed salvaged wound blood (SWB). RESULTS: At 30% hematocrit, SWB contained 2,162 +/- 147 leukocytes/microl. In comparison with venous blood, CD11b was up-regulated in SWB 1.3- to 3.6-fold on monocytes and neutrophils, whereas L-selectin and CD18 decreased on monocytes by 53% and 15%, respectively (P < 0.05). Despite up-regulation of CD11b, firm adhesion was significantly reduced by 74-76% in SWB. Rolling fractions and rolling velocities were significantly higher in SWB, and their relation to shear rate was markedly altered (P < 0.01). In addition, adherent leukocytes from SWB were significantly less resistant to increments of shear rate than leukocytes from venous blood (P < 0.01). CONCLUSIONS: Despite up-regulated CD11b, integrin-mediated adhesion is markedly impaired in salvaged blood. Therefore, the effect of blood salvage cannot be predicted from cell surface expression but rather from functional assays. The former hypothesis, that leukocytes from SWB aggravate leukocyte-mediated tissue injury by increased adhesion, may not be as great a concern as previously suggested.
Aged↗
Wavelet analysis of cutaneous blood flow in melanocytic skin lesions.
Laser Doppler flowmetry (LDF) is frequently used to study the microcirculation. Usually LDF time series are analyzed by conventional linear methods, mainly Fourier analysis. The aim of this study was to observe dynamic blood perfusion of the skin in malignant and benign melanocytic skin lesions. Wavelet transformation was performed on each LDF time series in order to calculate a vasomotion field. First, the differences in vasomotion between healthy and pigmented skin were evaluated visually on six different time scales of the vasomotion field. In order to quantify the findings, vasomotion scale variance (VSV) was calculated for each scale plane of the vasomotion field. These VSV were compared using contrast DeltaVSV to determine the difference between healthy skin and a pigmented skin lesion in the same patient. After the measurements, the skin lesions were excised and examined histologically. We found that wavelet analysis of LDF time series is a specific, sensitive method for the in vivo identification of malignant melanoma. It is a non-invasive procedure and takes minimal time to be carried out.
Humans↗
Evaluation of IL-8-concentrations in plasma and lysed EDTA-blood in healthy neonates and those with suspected early onset bacterial infection.
Plasma IL-8 is a diagnostic parameter of early-onset bacterial infection (EOBI) in neonates but has a short half-life. The detergent-lysed whole-blood (DLWB) IL-8 consists of both extracellular and cell-bound IL-8. The objective of this study was to investigate kinetics of plasma and DLWB IL-8 in healthy newborns and those with suspected EOBI and to test the hypothesis that determination of DLWB IL-8 results in higher sensitivity for EOBI detection. Sixty-one neonates with clinical and serologic signs of EOBI composed the study group; 188 neonates with risk factors but without EOBI served as control subjects. IL-8 concentrations were determined in plasma and DLWB. In the control group, DLWB IL-8 concentrations were 280-fold higher (9599 pg/mL; SD 4433) up to 24 h post partum than corresponding plasma levels (34.2 pg/mL; SD 18.1). The sensitivity of DLWB versus plasma IL-8 for EOBI was 0.97 versus 0.71 after 6 h and 0.70 versus 0.32 after 24 h. Corresponding values for specificity were 0.95 versus 0.90 after 6 h and 0.92 versus 0.99 after 24 h. After 24 h, the negative predictive value for DLWB versus plasma IL-8 was 0.80 versus 0.66. DLWB IL-8 showed a higher sensitivity for EOBI within 6 h after first clinical suspicion than plasma IL-8. It also remained elevated longer. Our results suggest that DLWB IL-8 results in a higher sensitivity for EOBI.
Age of Onset↗
Modeling senescence in hypotrichous ciliates.
A sexually reproducing hypotrichous ciliates undergo senescence which is in general attributed to degenerative processes in the macronucleus, assuming that loss of viability is based on loss of genetic elements. It is generally accepted that the genetic elements in the macronucleus of hypotrichs segregate randomly, a process which potentially can lead to aneuploid imbalances in the distribution of gene copies. It is, however, unclear whether there are mechanisms which compensate for such imbalances such that each genetic element regains its predetermined copy number (regulatory model, conserving euploidy), or whether the genetic elements only double, so that genetic imbalances can be inherited to further generations (stochastic model, allowing aneuploidy). By means of mathematical modeling and simulations, we investigate these two models with respect to the number of generations a lineage of hypotrichs can survive under asexual conditions. Whereas the regulatory model cannot explain senescence in hypotrichs, the stochastic model provides plausible results which, however, strongly depend on the assumed distribution of copy numbers which we investigate by means of three examples. For both models, simple prediction formulae for the approximate survival time of asexually reproducing ciliates are provided.
Aging↗
Smallpox: a vulnerable specter.
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Bioterrorism↗
Analysis of historical data suggests long-lasting protective effects of smallpox vaccination.
More than half of the US population has received the smallpox vaccine, but it is unknown what fraction is still protected against infection and disease. Residual protection and age-dependent case-fatality ratios have therefore been widely neglected in the current bioterrorism debate. The author analyzed 1902-1903 data from Liverpool, United Kingdom, and from reintroductions of the disease to Europe in 1950-1971 to estimate to what degree vaccinated cases were protected against developing severe or fatal disease and how quickly this protection waned over time. Protection against severe and fatal disease was lost at the rate of 1.41% per year, corresponding to a half-life of 49.2 years (95% confidence interval: 42.0, 57.3), and protection against fatal disease alone declined 0.363% per year. Thus, even 70 years after primary vaccination, 77.6% of cases were still protected (95% confidence interval: 66.6, 85.4). Protection against severe disease should therefore extend for many decades after a single vaccination, and protection against death from smallpox may even be lifelong for the majority of vaccinees. This protection should greatly reduce the number of severe and fatal cases of disease expected in a bioterrorist attack, but residual protection may also increase the risk that some previously vaccinated cases who develop mild disease may remain unrecognized longer, while moving around freely and disseminating the infection.
Adolescent↗
Transmission potential of smallpox: estimates based on detailed data from an outbreak.
Recent discussions on the use of variola virus by bioterrorists have rekindled interest in the parameters that govern the transmissibility of smallpox. Here, the authors estimate by maximum likelihood the parameters of the spread of smallpox from historical data on an epidemic in 1967 in the town of Abakaliki, Nigeria, afflicting a religious group that refused vaccination. According to the authors' estimates, 79.9% (95% confidence interval (CI): 63.6, 87.9) of the infectious contacts occurred within the compounds of the cases and 93.3% (95% CI: 80.6, 98.8) among compound members and other close contacts. Each case had 0.164 (95% CI: 0, 1.31) sufficiently close contacts on average during the fever period that preceded the rash and 6.87 (95% CI: 4.52, 10.1) sufficiently close contacts during the whole course of infectivity. These results support the widely held belief that smallpox spreads slowly, mainly among close contacts, and that infectivity before the onset of rash was negligible.
Adolescent↗
Case isolation and contact tracing can prevent the spread of smallpox.
Fears that terrorist groups may have gained access to variola virus have led to widespread discussions on how to prevent the reintroduction of smallpox by vaccination and on the availability of sufficiently large amounts of vaccine. In this paper, the author examines how the spread of smallpox is affected by isolating overt cases and taking their contacts under close surveillance for up to 3 weeks. The author assumes that case detection gradually improves from initially 7 days to 3 days. This intervention should be accompanied by vaccination, but its outcome does not depend on the vaccine's efficacy. It may, therefore, be especially important in controlling outbreaks caused by pathogens whose immunologic properties have been modified by genetic engineering. Using stochastic computer simulations, the author demonstrates that contact tracing and case isolation can extinguish smallpox outbreaks in highly susceptible populations within less than half a year without causing totals of more than 550 secondary cases per 100 index cases. The author also derives simple approximate expressions that allow prognostication on how efficiently an outbreak can be controlled by the described measures alone and prediction of the expected number of cases in an outbreak and the number of people that must be taken under surveillance.
Biological Warfare↗