Guiding equitable prioritisation of COVID-19 vaccine distribution and strategic deployment in South Africa to enhance effectiveness and access to vulnerable communities and prevent waste.

BACKGROUND: In South Africa (SA), >2.4 million cases of COVID­19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country's 52 districts to various extents. SA has committed to a COVID­19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. OBJECTIVES: To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID­19 epidemic control by reducing the number of COVID­19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. METHODS: For the 52 districts of SA, 26 COVID­19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID­19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. RESULTS: Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. CONCLUSIONS: The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.

Guiding equitable prioritisation of COVID-19 vaccine distribution and strategic deployment in South Africa to enhance effectiveness and access to vulnerable communities and prevent waste

Background. In South Africa (SA), >2.4 million cases of COVID­19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country's 52 districts to various extents. SA has committed to a COVID­19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. Objectives. To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID­19 epidemic control by reducing the number of COVID­19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. Methods. For the 52 districts of SA, 26 COVID­19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID­19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. Results. Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. Conclusions. The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.

Long-lasting disabling photophobia after uneventful cataract surgery.

The case concerns a 54-year-old woman, with a history of fibromyalgia and normal preoperative ocular and systemic study, who presented with a long-lasting disabling photophobia, after sequential bilateral cataract surgery without complications. Photophobia was accompanied by good uncorrected VA, with no pain or subjective eye discomfort, without migraine or indicators of psychic conflict. It was refractory to any prescribed treatment of the ocular surface, finally responding to oral anticonvulsants (carbamazepine) that are frequently used in neuropathic pain. To the best of our knowledge this is the first reported case of a long-lasting disabling photophobia without pain and good VA after cataract surgery.

Fotofobia invalidante de larga duración tras cirugía no complicada de cataratas / Long-lasting disabling photophobia after uneventful cataract surgery

Paciente mujer, de 54 años, con antecedente de fibromialgia y estudio preoperatorio ocular y sistémico normal, que presenta fotofobia invalidante de larga duración, tras cirugía bilateral secuencial de cataratas sin complicaciones. La fotofobia se acompañaba de buena AV no corregida, sin dolor ni molestias subjetivas oculares y sin migraña ni indicadores de conflictos psíquicos. Fue refractaria a cualquier tratamiento de la superficie ocular pautado, respondiendo finalmente a anticonvulsivantes orales (carbamazepina) frecuentemente utilizados en dolor de tipo neuropático. Según nuestro conocimiento es el único caso descrito de fotofobia invalidante de larga duración sin dolor y buena AV tras cirugía de cataratas (AU)

The case concerns a 54-year-old woman, with a history of fibromyalgia and normal preoperative ocular and systemic study, who presented with a long-lasting disabling photophobia, after sequential bilateral cataract surgery without complications. Photophobia was accompanied by good uncorrected VA, with no pain or subjective eye discomfort, without migraine or indicators of psychic conflict. It was refractory to any prescribed treatment of the ocular surface, finally responding to oral anticonvulsants (carbamazepine) that are frequently used in neuropathic pain. To the best of our knowledge this is the first reported case of a long-lasting disabling photophobia without pain and good VA after cataract surgery (AU)

Economic growth as an underlying probable systemic driver for childhood obesity in South Africa: A Joinpoint regression and ecological analysis over 10 years.

BACKGROUND: Childhood obesity has become a global public health problem and is a known risk factor for type 2 diabetes, cardiovascular disease, hypertension, stroke, myocardial infarction and various cancers in later adulthood.Associations between adult obesity and economic growth, technological changes, socioeconomic status and economic inequities have been reported, but limited data are available for children and adolescents in countries that are undergoing an epidemiological health transition exhibiting both under- and overnutrition. OBJECTIVES: To demonstrate childhood obesity trends and explore their associations with economic growth in South Africa (SA). METHODS: This was a retrospective review and analysis of obesity and economic growth trends in SA. Data for obesity levels were obtained from national surveys conducted in SA youths in 2002, 2008 and 2012. Economic growth indicators (EGIs), namely gross domestic product (GDP) per capita, household final consumption expenditure and Gini coefficient, were obtained from the World Bank and IHS Global Insight databases. Obesity trends for 2002 - 2012 are presented by gender and ethnicity. Annual percentage changes (APCs) in obesity prevalence were computed to assess obesity trends using the linear Joinpoint regression. RESULTS: An overall increase in obesity prevalence over time from 3.8% to 6.0% was observed. Females had higher levels across all time points. APCs in both males (7.8%; 95% confidence interval (CI) 0.3 - 15.9; p=0.01) and females (3.1%; 95% CI -14.7 - 24.7; p=0.30) were observed. Among black Africans, coloureds and whites, females had higher obesity levels than males for the three time points. For males, the prevalence of obesity was highest in whites and Asians/Indians, whereas coloureds and blacks had lower levels across all time points. However, the black male population had the highest APC increase (9.4%; 95% CI -23.0 - 55.3; p=0.20). The prevalence of obesity was positively and inversely associated with GDP per capita and the Gini coefficient, respectively. CONCLUSIONS: An increase in childhood and adolescent obesity over time was observed, while trend associations between obesity and EGIs exist.

Outcomes of community-based differentiated models of multi-month dispensing of antiretroviral medication among stable HIV-infected patients in Lesotho: a cluster randomised non-inferiority trial protocol.

BACKGROUND: Current World Health Organization (WHO) guidelines recommend early initiation of HIV positive patients on antiretroviral therapy (ART) irrespective of their clinical or immunological status known as the test and start approach. Lesotho, like many other countries introduced this approach in 2016 as a strategy to reach epidemic control. There will be rapidly growing number of HIV-infected individuals initiating treatment leading to practical challenges on health systems such as congestion, long waiting time for patients and limited time to provide quality services to patients. Differentiated models of ART delivery is an innovative solution that helps to increase access to care, while reducing the burden on existing health systems. Ultimately this model will help to achieve retention and viral suppression. We describe a demonstration study designed to evaluate a community-based differentiated model of multi-month dispensing (MMD) approaches of ART among stable HIV patients in Lesotho. METHODS: This study will be a three-arm cluster randomised trial, which will enrol approximately 5760 HIV-infected individuals who are stable on ART in 30 selected clusters. The clusters, which are health facilities, will be randomly assigned into the following differentiated model of care arms: (i) 3 monthly ART supply at facilities (Control), (ii) 3 monthly ART supply through community ART groups (CAGs) and (iii) 6 monthly ART supply through community ART distribution points (CAD). Primary outcomes are retention in care and virologic suppression, and secondary outcomes include feasibility and cost effectiveness. DISCUSSION: Important lessons will be learnt to allow for improved implementation of such demonstration projects, including various needs for reliable supply of medication, access to quality clinical data including access to viral loads (VLs) results, frameworks to support lay worker cadre, involvement of community stakeholders, and reliable data systems including records of key indicators. MMD will have positive implications including improved retention, virologic suppression, convenience and access to medication. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03438370 . Accepted on 16 February 2018.

Breast cancer trends differ by ethnicity: a report from the South African National Cancer Registry (1994-2009).

Background: To describe breast cancer (BC) incidence and mortality by ethnicity in South Africa (SA). Methods: Sources of data included the South African National Cancer Registry (NCR) pathology-based reports (1994­2009) and Statistics South Africa (SSA) mortality data (1997­2009). Numbers of cases, age-standardised incidence rates (ASIR) and lifetime risk (LR) were extracted from the NCR database for 1994­2009. Age-specific incidence rates were calculated for five-year age categories. The direct method of standardisation was employed to calculate age-standardised mortality rates (ASMR) using mortality data. Results: Between 1994 and 2009, there were 85 561 female BC. For the Black, Coloured and Asian groups, increases in ASIR and LR were observed between 1994 and 2009. In 2009, the ASIR for the total population, Blacks, Whites, Coloureds and Asians were 26.9, 18.7, 50.2, 40.9 and 51.2 per 100 000, respectively. For Asians, an increase in proportion of BC as a percentage of all female cancers was observed between 1994 and 2002 (11.1%) and continued to increase to 2009 (a further 4.5%). Whites and Asians presented higher incidences of BC at earlier ages compared with Blacks and Coloureds in 2009. In 1998, there were 1618 BC deaths in SA compared with 2784 deaths in 2009. ASMR between 1997 and 2004 increased but stabilised thereafter. Conclusion: This paper demonstrated that SA BC incidence rates are similar to other countries in the region, but lower than other countries with similar health systems. Ethnic differences in BC trends were observed. However, the reasons for observed ethnic differences are unclear.

A comparison of body composition estimates using dual-energy X-ray absorptiometry and air-displacement plethysmography in South African neonates.

BACKGROUND/OBJECTIVES: Neonatal body composition is an important predictor of future metabolic risk; however, the comparability of objective assessment techniques, particularly in African populations undergoing rapid health transition, is not known. This paper compares body composition estimates by air-displacement plethysmography (ADP) and dual-energy X-ray absorptiometry (DXA) in South African neonates. SUBJECTS/METHODS: Fat mass, fat-free mass and body fat percentage (%fat) estimates by ADP and DXA were compared in 88 urban, black South African neonates. The level of agreement between the techniques was assessed using Bland-Altman analyses. RESULTS: Significant correlations were observed between ADP and DXA measurements of fat mass (r=0.766), fat-free mass (r=0.942) and %fat (r=0.630); however, ADP estimates of fat mass (408±172 g vs 337±165 g; P<0.001) and %fat (12.9±4.4% vs 9.9±4%; P<0.001) were significantly higher and fat-free mass (2681±348 g vs 2969±375 g; P<0.001) significantly lower than those by DXA. Fat-free mass estimates showed greater consistency in the level of agreement between the techniques compared with fat and %fat estimates where the differences between methods were less predictable. CONCLUSION: Although ADP and DXA body composition estimates are highly correlated in neonates, significant differences are observed between the techniques. This is particularly relevant for fat mass and %fat estimates, where differences are highly variable between methods. Further investigation is needed to minimise inter-method differences to ensure accurate and comparable assessment of body composition at birth and across longitudinal study follow-up.

Relationship between early growth and CVD risk factors in adolescents.

Low birth weight and a rapid weight gain in early childhood may lead to an increased risk for developing cardiovascular disease later in life, such as hypertension and dyslipidaemia. In this study, we examined the associations between size at birth, relative weight gain in infancy and childhood with specific cardiovascular disease risk factors in early adulthood. Adolescents (n=1935) from the Birth to Twenty plus (BT20+) cohort were included in the analysis. The following were treated as exposure variables: weight at birth, and relative conditional weight gain (CW), independent of height, between ages 0-24 months and 24-48 months. Outcomes were serum lipids and body composition variables at age 18 years. After adjusting for sex and other confounders, early life exposures were not associated with adolescent lipid profile. Following adjustment for sex and height (body size), birth weight [ß=0.704 (0.40, 1.01)], CW 0-24 [ß=1.918 (1.56, 2.28)] and CW24-48 [ß=1.485 (1.14, 1.82)] accounted for 48% of the variance in fat mass. However, birth weight [ß=0.773 (0.54, 1.01)], CW 0-24 [ß=1.523 (1.24, 1.80)] and CW24-48 [ß=1.226 (0.97, 1.49)] were also positively predicted and accounted for 71% of the variance in fat mass in adolescence (P<0.05). Our data suggests that birth weight and weight gain during infancy and early childhood independent of linear growth are related to adolescent body composition but not blood lipid profiles in an urban African population.

Review of the importance of nutrition during the first 1000 days: maternal nutritional status and its associations with fetal growth and birth, neonatal and infant outcomes among African women.

Maternal nutritional status (MNS) is a strong predictor of growth and development in the first 1000 days of life and may influence susceptibility to non-communicable diseases in adulthood. However, the role of nutrition during this window of developmental plasticity in Africa is unclear. This paper reviews published data to address whether maternal nutrition during the first 1000 days is important for Africa, with a focus on MNS and its associations with fetal growth and birth, neonatal and infant outcomes. A systematic approach was used to search the following databases: Medline, EMBASE, Web of Science, Google Scholar, ScienceDirect, SciSearch and Cochrane Library. In all, 26 studies met the inclusion criteria for the specific objectives. MNS in Africa showed features typical of the epidemiological transition: higher prevalences of maternal overweight and obesity and lower underweight, poor diet quality 1 and high anaemia prevalence. Maternal body mass index and greater gestational weight gain (GWG) were positively associated with birth weight; however, maternal overweight and obesity were associated with increased risk of macrosomia and intrauterine growth restriction. Maternal anaemia was associated with lower birth weight. Macro- and micronutrient supplementation during pregnancy were associated with improvements in GWG, birth weight and mortality risk. Data suggest poor MNS in Africa and confirms the importance of the first 1000 days as a critical period for nutritional intervention to improve growth, birth outcomes and potential future health risk. However, there is a lack of data beyond birth and a need for longitudinal data through infancy to 2 years of age.

Mechanisms of stress, energy homeostasis and insulin resistance in European adolescents--the HELENA study.

BACKGROUND AND AIMS: Stress is hypothesized to facilitate the development of obesity, whose the foundations are already set during childhood and adolescence. We investigated the relationship between the stress-system, selected mechanisms of energy homeostasis and insulin resistance (IR) in a sample of European adolescents. METHODS AND RESULTS: Within HELENA-CSS, 723 adolescents (12.5-17.5 years) from 10 European cities provided all the necessary data for this study. Fasting blood samples were collected for cortisol, leptin, insulin and glucose analysis. HOMA-IR was calculated from insulin and glucose concentrations. Adolescents' body fat (BF) %, age and duration of exclusive breastfeeding were assessed. For boys and girls separately, the relationship of cortisol with leptin, insulin, glucose and HOMA-IR was examined by computing Pearson correlation coefficients and Hierarchical Linear Models (HLMs), with 'city' as cluster unit, adjusting for age, BF% and duration of exclusive breastfeeding. In boys, Pearson correlation coefficients illustrated positive correlations of cortisol with insulin (r = 0.144; p = 0.013), glucose (r = 0.315; p < 0.001) and HOMA-IR (r = 0.180; p = 0.002), whilst in girls, this positive relationship was observed for leptin (r = 0.147; p = 0.002), insulin (r = 0.095; p = 0.050) and HOMA-IR (r = 0.099; p = 0.041), but not for glucose (r = 0.054; p = 0.265). Observed associations were independent of adolescents' age, BF% and duration of exclusive breastfeeding after computing HLMs. CONCLUSION: This study suggests that the stress-system is positively related to mechanisms of energy homeostasis and IR in European adolescents, and reveals a potential small gender difference in this relationship. The hypothesis that stress might facilitate the development of obesity during adolescence is supported.

Social drift of cardiovascular disease risk factors in Africans from the North West Province of South Africa: the PURE study.

OBJECTIVE: This study examined whether the association between socio-economic status (SES) and cardiovascular disease (CVD) risk factors in black South Africans from the North West Province had shifted from the more affluent groups with higher SES to the less affluent, lower SES groups over a period of nine years. METHOD: Cross-sectional baseline data of 2 010 urban and rural subjects (35 years and older) participating in the Prospective Urban and Rural (PURE) study and collected in 2005 were analysed to examine the relationship of level of education, employment and urban or rural residence with dietary intakes and other CVD risk factors. These relationships were compared to those found nine years earlier in the Transition and Health during the Urbanisation of South Africans (THUSA) study conducted in the same area. RESULTS: The results showed that urban women had higher body mass index (BMI), serum triglyceride and fasting glucose levels compared to rural women and that both urban men and women had higher blood pressures and followed a more Westernised diet. However, rural men and women had higher plasma fibrinogen levels. The more highly educated subjects (which included both urban and rural subjects) were younger than those with no or only primary school education. Few of the risk factors differed significantly between education groups, except that more highly educated men and women had lower BMIs, and women had lower blood pressure and triglyceride levels. These women also followed a more prudent diet than those with only primary school education. Employed men and women had higher BMIs, higher energy intakes but lower plasma fibrinogen levels, and employed women had lower triglyceride levels. No significant differences in total serum cholesterol values were observed. CONCLUSION: These results suggest a drift of CVD risk factors from groups with higher SES to groups with a lower SES from 1996 to 2005, indicating that interventions to prevent CVD should also be targeted at Africans living in rural areas, those with low educational levels, and the unemployed.

The relationship between indices of iron status and selected anthropometric cardiovascular disease risk markers in an African population: the THUSA study.

There is evidence that certain indices of iron status are associated with anthropometric measures, which are used independently as markers of cardiovascular disease (CVD) risk. This study examined whether this association exists in an African population. The study was a cross-sectional comparative study that examined a total of 1 854 African participants. Ferritin was positively associated with body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), percentage body fat and subscapular skinfold thickness. Serum ferritin concentration was higher in the high-WHR category than the normal-WHR category for both genders. Additionally, WC and WHR increased with increasing ferritin concentrations in both genders. Serum iron was lower in the obese than the normal-weight and pre-obese women only. In this population-based study, increased serum ferritin concentrations associated positively with increased WHR and WC, indicating that individuals or populations at risk of iron overload as defined by high serum ferritin concentrations may be at a greater risk of developing CVD.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

Generation of DC-based vaccine for therapy of B-CLL patients. Comparison of two methods for enriching monocytic precursors.

BACKGROUND: The generation of Ag-loaded DC under good manufacturing practice (GMP) conditions is logistically challenging and further compounded when the starting precursors need to be purified from B-CLL patients who have overwhelming numbers of circulating B-CLL cells and decreased numbers of monocytes. METHODS: We have previously demonstrated that DC with endocytosed B-CLL apoptotic bodies are powerful stimulators of anti-leukemic T cells. In this study we compared counterflow elutriation and immunomagnetic separation for enriching monocyte precursors, and evaluated the feasibility of generating DC from B-CLL patients and the effects of cryopreservation. RESULTS: Monocyte yield from a single leukapheresis product of a B-CLL patient varied from 1 x 108 to 10 x 108 total cells, from which 40-200 x 106 mature DC could be produced. Adequate numbers of monocytes could not be enriched from one patient with 0.2% monocytes in the leukapheresis product, and the target of 50 x 106 DC was barely achieved in another patient with 0.9% monocytes in the pheresed cells. These results suggested that successful production of DC is dependent on a minimum frequency of 1% CD14(+) monocytes in the leukapheresis product. Cryopreservation of tumor cell-loaded DC yielded a recovery rate of 86+/-4.4% upon thawing, with a total viability of 90+/-2.8%. Most importantly, cryopreserved Ag-loaded DC retained their morphology, phenotype and function. DISCUSSION: The results demonstrate that adequate numbers of functional DC required for clinical therapy can be generated from patients who have >1% of CD14(+) monocytes in the leukapheresis product. Moreover, Ag-loaded DC can be cryopreserved and recovered without significant change in phenotype or function.

Effects of human plasma proteins on maturation of monocyte-derived dendritic cells.

Dendritic cells (DC) are a promising tool for vaccine therapy due to their unique properties as antigen presenting cells and their ability to prime naïve T cells. Increasing evidence suggests that maturation stage of DC critically influences the fate of the immune response. Generation of monocyte-derived DC for clinically applicable immunotherapy requires the use of well-defined components and stringent culture conditions. An alternative strategy is to use human autologous serum. However, its constituents are not stable and reflect the inflammatory condition of the donor. In order to investigate whether DC properties are influenced by proteins present in the plasma, we matured human monocyte-derived DC with four main plasma components: fibrinogen, fibronectin, plasminogen or C-reactive protein. These purified proteins were added at various concentrations on day 6 after the initial differentiation induced by IL-4 and GM-CSF. The maturation was assessed by phenotyping of maturation-associated marker (CD83) and co-stimulatory molecule CD86 as well as IL-12 production. Functional properties of DC were assessed by endocytic activity and mixed leukocyte culture. Our results indicate that fibrinogen had DC-maturation effect comparable to poly-I:C, TNF-alpha and PGE(2) as a positive control, but it failed to induce IL-12 production. The other plasma proteins had no effect on DC maturation. CRP at high concentration had rather inhibitory effect on DC induced lymphocyte function. We conclude that none of the tested plasma components and acute phase proteins sufficiently induce fully competent mature DC. This finding is important for the preparation of human DC-based vaccines supplemented by autologous sera.

A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer.

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 microg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-gamma production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-gamma production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 microg the vaccine can induce cellular and humoral immune responses against PSA protein.

Development of a technology platform for large-scale clinical grade production of DC.

BACKGROUND: Clinical studies require protocols where a sufficient number of well-characterized highly immunogenic DC are produced according to good manufacturing practice (GMP) guidelines. METHODS: In the present study, using leukapheresis products from 10 cancer patients, we validated an elutriation technology for large-scale clinical grade production of monocyte-derived DC. RESULTS: The elutriation method gave a very high purity (mean+/-SD) (86+/-5.3%) and recovery (66+/-10.4%) of monocytes. Specifically for the two monocyte-rich fractions (3 and 4,) the recovery was 42+/-13% of viable cells that could be further differentiated into immature DC in hydrophobic culture bags using GM-CSF and IL-4. The immature DC exhibited<1% CD83+ expression and >98% phagocytic activity. Maturation with TNF-alpha or poly I:C resulted in DC with expression of CD80+, CD86+ and HLA-DR+ (>99%) and CD83+ (80+/-11.9%), as well as producing IL-12p70 and lacking phagocytic activity (<5%). This cell product can be cryopreserved with cell viability >85% and cell recovery >80% after thawing. DISCUSSION: The elutriation procedure, when optimized and if the monocyte content of the starting material exceeds 5%, does not require further selection or depletion using affinity approaches.

Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma.

We have evaluated whether allogeneic hematopoietic stem cell transplantation (HSCT) could induce an antitumor effect in patients with metastatic solid tumors. A total of 12 HLA-identical siblings and 6 HLA-A-, -B- and -DR beta 1-compatible unrelated grafts were used. Diagnoses were adenocarcinoma of kidney (n=10), colon (n=6), breast (n=1) and cholangiocarcinoma (n=1). Conditioning was fludarabine 30 mg/m(2)/day for 3 days and 2 Gy of total body irradiation. Recipients of unrelated HSCT were also given thymoglobuline and two additional days of fludarabine. The median CD34+ cell dose was 7.5 x 10(6)/kg. Immunosuppression was mycophenolate mofetil and cyclosporin. Among all, 12 patients became complete donor chimeras within a median of 28, 29 and 65 days for B, myeloid and T cells, respectively. Two patients rejected the grafts, one developed marrow aplasia and three were mixed chimeras. The probability of grades II-IV acute graft-versus-host-disease (GVHD) was 57%. Regression of all tumor metastases was seen in one patient with colon carcinoma. Another patient with colon and two with renal carcinoma had regression of lung metastases, but progression of metastases in the liver and/or bone. Necrosis of lung metastasis was found in one further patient with renal carcinoma who died of graft-versus-host-disease (GVHD). In all, 10 patients died; four of transplant-related complications, one of trauma and five of progressive disease. Thus, progression was common after allogeneic HSCT in unselected patients with advanced solid tumors. However, the regression of some metastases associated with GVHD provides suggestive evidence that the GVHD effect may occur in renal and colon adenocarcinoma using reduced intensity conditioning.