Urban Policies and Health In Developing Countries: The Case of Maputo (Mozambique) and Cochabamba (Bolivia)

Urban planning and related policies can contribute to improvement in health. Recent epidemiological and quantitative Health Impact Assessment (HIA) studies in Europe and North America suggest that a change from passive (car) to active transportation (cycling, walking) and public transport in daily life could improve health. HIA studies are still largely lacking in low and middle-income countries. We conducted a scoping study to evaluate the availability of data to conduct quantitative HIA in two cities from two low-income countries. We collected information through interviews with different local agents, from the National Institute of Statistics and by conducting field work to identify the built environment and mobility characteristics in the respective cities. Conducting a quantitative HIA in Maputo (Mozambique) is currently not possible, mainly because there is no appropriate data on mortality, road traffic accidents and physical activity of the general population. However, in Cochabamba (Bolivia) it might be possible when the mobility plan will be available (currently under development), in which data on traffic flows, mobility surveys and transport modal shares will become available. The current paper describes two examples of the opportunities and difficulties to conduct quantitative HIA in low- and middle-income countries, highlighting the limited availability of data (quantitatively and qualitatively) on transport and urban planning and health outcomes

Long-lasting insecticidal nets no longer effectively kill the highly resistant Anopheles funestus of southern Mozambique

BACKGROUND: Chemical insecticides are crucial to malaria control and elimination programmes. The frontline vector control interventions depend mainly on pyrethroids; all long-lasting insecticidal nets (LLINs) and more than 80% of indoor residual spraying (IRS) campaigns use chemicals from this class. This extensive use of pyrethroids imposes a strong selection pressure for resistance in mosquito populations, and so continuous resistance monitoring and evaluation are important. As pyrethroids have also been used for many years in the Manhica District, an area in southern Mozambique with perennial malaria transmission, an assessment of their efficacy against the local malaria vectors was conducted. METHODS: Female offspring of wild-caught Anopheles funestus s.s. females were exposed to deltamethrin, lambda-cyhalothrin and permethrin using the World Health Organization (WHO) insecticide-resistance monitoring protocols. The 3-min WHO cone bioassay was used to evaluate the effectiveness of the bed nets distributed or available for purchase in the area (Olyset, permethrin LLIN; PermaNet 2.0, deltamethrin LLIN) against An. funestus. Mosquitoes were also exposed to PermaNet 2.0 for up to 8 h in time-exposure assays. RESULTS: Resistance to pyrethroids in An. funestus s.s. was extremely high, much higher than reported in 2002 and 2009. No exposure killed more than 25.8% of the mosquitoes tested (average mortality, deltamethrin: 6.4%; lambda-cyhalothrin: 5.1%; permethrin: 19.1%). There was no significant difference in the mortality generated by 3-min exposure to any net (Olyset: 9.3% mortality, PermaNet 2.0: 6.0%, untreated: 2.0%; p = 0.2). Six hours of exposure were required to kill 50% of the An. funestus s.s. on PermaNet 2.0. CONCLUSIONS: Anopheles funestus s.s. in Manhica is extremely resistant to pyrethroids, and this area is clearly a pyrethroid-resistance hotspot. This could severely undermine vector control in this district if no appropriate countermeasures are undertaken. The National Malaria Control Programme (NMCP) of Mozambique is currently improving its resistance monitoring programme, to design and scale up new management strategies. These actions are urgently needed, as the goal of the NMCP and its partners is to reach elimination in southern Mozambique by 2020

Cytokine and antibody responses to Plasmodium falciparum in naïve individuals during a first malaria episode: effect of age and malaria exposure.

Age- and exposure-dependent immune responses during a malaria episode may be key to understanding the role of these factors in the acquisition of immunity to malaria. Plasma/serum samples collected from naïve Mozambican children (n = 48), European adults (naïve travelers, n = 22; expatriates with few prior malaria exposures, n = 15) and Mozambican adults with long-life malaria exposure (n = 99) during and after a malaria episode were analyzed for IgG against merozoite proteins by Luminex and against infected erythrocytes by flow cytometry. Cytokines and chemokines were analyzed in plasmas/sera by suspension array technology. No differences were detected between children and adults with a primary infection, with the exception of higher IgG levels against 3D7 MSP-142 (P = 0.030) and a P. falciparum isolate (P = 0.002), as well as higher IL-12 (P = 0.020) in children compared to other groups. Compared to malaria-exposed adults, children, travelers and expatriates had higher concentrations of IFN-γ (P≤0.0090), IL-2 (P≤0.0379) and IL-8 (P≤0.0233). Children also had higher IL-12 (P = 0.0001), IL-4 (P = 0.003), IL-1β (P = 0.024) and TNF (P = 0.006) levels compared to malaria-exposed adults. Although IL-12 was elevated in children, overall the data do not support a role of age in immune responses to a first malaria episode. A TH1/pro-inflammatory response was the hallmark of non-immune subjects

A balanced pro-inflammatory and regulatory cytokine signature in young African children is associated with lower risk of clinical malaria

Background: The effect of timing of exposure to first Plasmodium falciparum infections during early childhood on the induction of innate and adaptive cytokine responses and their contribution to the development of clinical malaria immunity is not well established. Methods: As part of a double-blind randomized placebo-controlled trial in Mozambique using monthly chemoprophylaxis with sulfadoxine-pyrimethamine plus artesunate to selectively control timing of malaria exposure during infancy, peripheral blood mononuclear cells collected at ages 2.5, 5.5, 10.5, 15 and 24 months were stimulated ex vivo with parasite schizont and erythrocyte lysates. Cytokine mRNA expressed in cell pellets and proteins secreted in supernatants were quantified by real time quantitative PCR and multiplex flow cytometry, respectively. Children were followed up for clinical malaria from birth until 4 years of age. Results: Higher pro-inflammatory (IL-1, IL-6, TNF) and regulatory (IL-10) cytokine concentrations during the second year of life were associated with reduced incidence of clinical malaria up to 4 years of age, adjusting by chemoprophylaxis and prior malaria exposure. Significantly lower concentrations of antigen-specific TH1 (IL-2, IL-12, IFN-) and TH2 (IL-4, IL-5) cytokines by 2 years of age were measured in children under chemoprophylaxis compared to children receiving placebo (p<0.03). Conclusions: Selective chemoprophylaxis altering early natural exposure to malaria blood stage antigens during infancy had a significant effect on TH lymphocyte cytokine production more than one year later. Importantly, a balanced pro-inflammatory and anti-inflammatory cytokine signature probably by innate cells around age 2 years was associated with protective clinical immunity during childhood

High antibody responses against Plasmodium falciparum in immigrants after extended periods of interrupted exposure to malaria.

Background Malaria immunity is commonly believed to wane in the absence of Plasmodium falciparum exposure, based on limited epidemiological data and short-lived antibody responses in some longitudinal studies in endemic areas. Methods A cross-sectional study was conducted among sub-Saharan African adults residing in Spain for 1 up to 38 years (immigrants) with clinical malaria (n=55) or without malaria (n=37), naïve adults (travelers) with a first clinical malaria episode (n=20) and life-long malaria exposed adults from Mozambique (semi-immune adults) without malaria (n=27) or with clinical malaria (n=50). Blood samples were collected and IgG levels against the erythrocytic antigens AMA-1 and MSP-142 (3D7 and FVO strains), EBA-175 and DBL-α were determined by Luminex. IgG levels against antigens on the surface of infected erythrocytes (IEs) were measured by flow cytometry. Results Immigrants without malaria had lower IgG levels than healthy semi-immune adults regardless of the antigen tested (P≤0.026), but no correlation was found between IgG levels and time since migration. Upon reinfection, immigrants with malaria had higher levels of IgG against all antigens than immigrants without malaria. However, the magnitude of the response compared to semi-immune adults with malaria depended on the antigen tested. Thus, immigrants had higher IgG levels against AMA-1 and MSP-142 (P≤0.015), similar levels against EBA-175 and DBL-α, and lower levels against IEs (P≤0.016). Immigrants had higher IgG levels against all antigens tested compared to travelers (P≤0.001), both with malaria. Conclusions Upon cessation of malaria exposure, IgG responses to malaria-specific antigens were maintained to a large extent, although the conservation and the magnitude of the recall response depended on the nature of the antigen. Studies on immigrant populations can shed light on the factors that determine the duration of malaria specific antibody responses and its effect on protection, with important implications for future vaccine design and public health control measures

IgM and IgG against Plasmodium falciparum lysate as surrogates of malaria exposure and protection during pregnancy

BACKGROUND: Difficulties to disentangle the protective versus exposure role of anti-malarial antibodies hamper the identification of clinically-relevant immune targets. Here, factors affecting maternal IgG and IgMs against Plasmodium falciparum antigens, as well as their relationship with parasite infection and clinical outcomes, were assessed in mothers and their children. Antibody responses among 207 Mozambican pregnant women at delivery against MSP119, EBA175, AMA1, DBLalpha and parasite lysate (3D7, R29 and E8B parasite lines), as well as the surface of infected erythrocytes, were assessed by enzyme-linked immunosorbent assay and flow cytometry. The relationship between antibody levels, maternal infection and clinical outcomes was assessed by multivariate regression analysis. RESULTS: Placental infection was associated with an increase in maternal levels of IgGs and IgMs against a broad range of parasite antigens. The multivariate analysis including IgGs and IgMs showed that the newborn weight increased with increasing IgG levels against a parasite lysate, whereas the opposite association was found with IgMs. IgGs are markers of protection against poor pregnancy outcomes and IgMs of parasite exposure. CONCLUSIONS: Adjusting the analysis for the simultaneous effect of IgMs and IgGs can contribute to account for heterogeneous exposure to P. falciparum when assessing immune responses effective against malaria in pregnancy

Safety, Immunogenicity and Duration of Protection of the RTS,S/AS02D Malaria Vaccine: One Year Follow-Up of a Randomized Controlled Phase I/IIb Trial

The RTS,S/AS02(D) vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D) given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D) and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D), remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003).The RTS,S/AS02(D) malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028

The Role of Age and Exposure to Plasmodium falciparum in the Rate of Acquisition of Naturally Acquired Immunity: A Randomized Controlled Trial

Background: The rate of acquisition of naturally acquired immunity (NAI) against malaria predominantly depends on transmission intensity and age, although disentangling the effects of these is difficult. We used chemoprophylaxis to selectively control exposure to P. falciparum during different periods in infancy and explore the effect of age in the build-up of NAI, measured as risk of clinical malaria.\ud \ud Methods and Findings: A three-arm double-blind randomized placebo-controlled trial was conducted in 349 infants born to Mozambican HIV-negative women. The late exposure group (LEG) received monthly Sulfadoxine-Pyrimethamine (SP) plus Artesunate (AS) from 2.5–4.5 months of age and monthly placebo from 5.5–9.5 months; the early exposure group (EEG) received placebo from 2.5–4.5 months and SP+AS from 5.5–9.5 months; and the control group (CG) received placebo from 2.5–9.5 months. Active and passive case detection (PCD) were conducted from birth to 10.5 and 24 months respectively. The primary endpoint was time to first or only episode of malaria in the second year detected by PCD. The incidence of malaria during the second year was of 0.50, 0.51 and 0.35 episodes/PYAR in the LEG, EEG and CG respectively (p = 0.379 for the adjusted comparison of the 3 groups). The hazard ratio of the adjusted comparison between the LEG and the CG was 1.38 (0.83–2.28, p = 0.642) and that between the EEG and the CG was 1.35 (0.81–2.24, p = 0.743).\ud \ud Conclusions: After considerably interfering with exposure during the first year of life, there was a trend towards a higher risk of malaria in the second year in children who had received chemoprophylaxis, but there was no significant rebound. No evidence was found that the age of first exposure to malaria affects the rate of acquisition of NAI. Thus, the timing of administration of antimalarial interventions like malaria vaccines during infancy does not appear to be a critical determinant

Exposure to organochlorine compounds at the aerly stages of DDT use for indoor residual spraying in domestic environments in Manhiça, Mozambique.

Past and present uses of DDT and pyrethroids have led to their incorporation into humans, mainly through the food chain and sometimes by direct exposure. The present work focuses on establishing the levels of DDT, its analogous compounds (DDE and DDD), and pyrethroids in humans and the human environment in Manhiça, a rural area where they have been used as insecticides for indoor residual spraying (IRS) and insecticide treated nets (ITN) in malaria control programs. Thatch samples from human dwellings, breast milk from pregnant women and cord blood from newborns were analyzed for assessment of the concentration levels of these compounds. The results showed that DDT and its analogues were already present in humans and dwellings before reintroduction of this insecticide for IRS. As consequence of these applications DDT concentrations increased significantly. The higher proportion of 4,4’-DDT than 4,4’-DDE evidenced that the observed amounts were due to recent applications of this insecticide. Concerning pyrethroids, their presence has been identified in both breast milk and human dwellings showing that both agricultural applications and use for ITN may be responsible for their occurrence in humans and human environments of Manhiça.L’ús en el passat i en temps actuals del DDT i piretroides ha donat lloc a la seva incorporació en els humans, principalment mitjançant la cadena tròfica i a vegades per exposició directa. Aquest treball té com objectiu establir els nivells de DDT i els seus compostos anàlegs (DDE i DDD), i piretroides en humans i l’ambient humà a Manhiça, una àrea rural on aquests s’han utilitzat com insecticides per aplicació interna (indoor residual spraying, IRS) i tractament de xarxes de protección (insecticide treated nets, ITN) en programes de control de la malària. Per a esbrinar els nivells de concentració d’aquests compostos s’analitzaren mostres de palla de cabanes, de llet materna i de sang de cordó de nou nats. Els resultats mostraren que el DDT i els seus compostos anàlegs ja eren presents en humans i cabanes abans de la reintroducció d’aquest insecticida per IRS. L’ús del DDT en aquest programa féu augmentar considerablement les concentracions d’aquest insecticida. La major proporció de 4,4’-DDT que 4,4’-DDE posà de manifest que les quantitats observades corresponien a aplicacions recents d’aquest insecticida. Respecte als piretroides, s’han trobat en mostres de llet materna i cabanes tot mostrant que tant les aplicacions agrícoles com el seu ús en ITN poder esser la causa de la seva presència en els humans i els ambients humans de Manhiça

Urban Policies and Health In Developing Countries: The Case of Maputo (Mozambique) and Cochabamba (Bolivia)

Urban planning and related policies can contribute to improvement in health. Recent epidemiological and quantitative Health Impact Assessment (HIA) studies in Europe and North America suggest that a change from passive (car) to active transportation (cycling, walking) and public transport in daily life could improve health. HIA studies are still largely lacking in low and middle-income countries. We conducted a scoping study to evaluate the availability of data to conduct quantitative HIA in two cities from two low-income countries. We collected information through interviews with different local agents, from the National Institute of Statistics and by conducting field work to identify the built environment and mobility characteristics in the respective cities. Conducting a quantitative HIA in Maputo (Mozambique) is currently not possible, mainly because there is no appropriate data on mortality, road traffic accidents and physical activity of the general population. However, in Cochabamba (Bolivia) it might be possible when the mobility plan will be available (currently under development), in which data on traffic flows, mobility surveys and transport modal shares will become available. The current paper describes two examples of the opportunities and difficulties to conduct quantitative HIA in low- and middle-income countries, highlighting the limited availability of data (quantitatively and qualitatively) on transport and urban planning and health outcomes