Increased HIV Incidence in Wuchereria bancrofti Microfilaria Positive Individuals in Tanzania.

BACKGROUND: Infections with Wuchereria bancrofti are associated with reduced immunity against concomitant infections. Indeed, our previous study described a 2.3-fold increased HIV incidence among individuals with W. bancrofti infection, as measured by the circulating filarial antigen of the adult worm. This new study aimed to retrospectively determine microfilariae status of the participants to assess if the previously described increased HIV susceptibility was associated with the presence of MF in the same cohort. METHODS: CFA positive but HIV negative biobanked human blood samples (n = 350) were analyzed for W. bancrofti MF chitinase using real time PCR. RESULTS: The PCR provided a positive signal in 12/350 (3.4%) samples. During four years of follow-up (1109 person years (PY)), 22 study participants acquired an HIV infection. In 39 PY of W. bancrofti MF chitinase positive individuals, three new HIV infections occurred (7.8 cases per 100 PY), in contrast to 19 seroconversions in 1070 PY of W. bancrofti MF chitinase negative individuals (1.8 cases per 100 PY, p = 0.014). CONCLUSIONS: In the subgroup of MF-producing Wb-infected individuals, the HIV incidence exceeded the previously described moderate increased risk for HIV seen in all Wb-infected individuals (regardless of MF status) compared with uninfected persons from the same area.

Building sustainable clinical trial sites in Sub-Saharan Africa through networking, infrastructure improvement, training and conducting clinical studies: The PanACEA approach.

INTRODUCTION: The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and four European research institutions. OBJECTIVES: In 2011, a capacity development program, funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), was launched with four objectives, aiming at strengthening collaborating TB research sites to reach the ultimate goal of becoming self-sustainable institutions: networking; training; conducting clinical trials; and infrastructure scaling-up of sites. METHODS: Assessment in six sub-Saharan TB-endemic countries (Gabon, Kenya, South Africa, Tanzania, Uganda and Zambia) were performed through a structured questionnaire, site visits, discussion with the PanACEA consortium, setting of milestones and identification of priorities and followed-up with evaluations of each site. The results of this needs-based assessment was then translated into capacity development measures. RESULTS: In the initial phase, over a four-year period (March 2011 - June 2014), the programme scaled-up six sites; conducted a monitoring training program for 11 participants; funded five MSc and four PhD students, fostering gender balance; conducted four epidemiological studies; supported sites to conduct five Phase II studies and formed a sustainable platform for TB research (panacea-tb.net). CONCLUSION: Our experience of conducting TB clinical trials within the PanACEA programme environment of mentoring, networking and training has provided a sound platform for establishing future sustainable research centres. Our goal of facilitating emergent clinical TB trial sites to better initiate and lead research activities has been mostly successful.

Development, Implementation, and Scale Up of the National Furaha Yangu Campaign to Promote HIV Test and Treat Services Uptake Among Men in Tanzania.

Evidence has demonstrated that immediate HIV treatment initiation upon a positive HIV test, referred to as Test and Treat, can help people living with HIV live longer, healthier lives and prevent HIV transmission. Although Tanzania adopted the evidence-based Test and Treat strategy since 2016, men were not being adequately reached for HIV services. A national campaign was launched to promote the new HIV services with a focus on men. To inform the development and implementation of the campaign, we conducted formative audience insights-gathering (AIG) sessions to assess facilitators and barriers to accessing HIV Test and Treat services and inform the concepts and materials for the campaign. Qualitative AIG interviews and focus group discussions were conducted with 54 people who were unaware or aware of their HIV status and currently or not currently on treatment, as well as health workers. Facilitators and barriers included a fear of testing positive, the desire to belong, control their narratives, and reinvent themselves to achieve their dreams and live a happy life. The campaign played off a My Happiness! creative concept to position antiretroviral therapy (ART) as a solution to fears around what life would be like after a positive HIV diagnosis. The development and implementation of the campaign were informed by the AIG sessions and national stakeholders, leading to strong partners' buy-in that supported the scale-up of the ongoing campaign from 12 to 26 regions via the collaborative efforts of government, donors, and implementing partners.

Perceived benefits, challenges, and recommendations for HIV research dissemination and implementation science efforts in Tanzania: Findings from the HIV/AIDS Research Forum brainstorming session.

Although several international and national HIV/AIDS conferences exist, there was not a national conference in Tanzania focusing on HIV/AIDS disseminating and implementation research conducted in the country and abroad. This created a missed opportunity for researchers to share their research findings with local policymakers and HIV program implementers who can influence the adoption and implementation of promising research in public health and clinical practice settings. In response, the first HIV/AIDS D&I Research Forum designed to enhance local D&I efforts for HIV research, was organized in Tanzania in 2018. This paper explores the perceived benefits of the HIV/AIDS D&I Research Forum and potential challenges of developing similar forums and recommendation for future HIV research D&I conference in Tanzania. During the second day of the Forum, which was held in September 2018 in Morogoro, Tanzania, a 1-hour structured brainstorming session was conducted with the Forum attendees (n = 50), including researchers, medical professionals, policymakers, representatives from different ministries. Transcription of the brainstorming session was analyzed to identify benefits of the Forum, perceived challenges for organizing similar HIV/AIDS research dissemination events, and recommendations for addressing the challenges. Overall, participants perceived the forum to be beneficial because it provided opportunities for strategic collaborations between researchers, policymakers, and other stakeholders and for them to discuss challenges for D&I efforts. Forum attendees also identified several potential challenges for future D&I research forums such as the abstract requirement which may deter non-researchers, costs, meeting frequencies, and lack of funding and coordination between organizations involved in D&I research efforts. To address these concerns, a recommendation was made to host a biennial national conference in order to allow more time for ethical review and feedback that can enhance contribution of the project to D&I efforts and to raise funds. The benefits identified for the Forum highlight the importance of organizing similar D&I meetings for HIV-related research at the national level in Tanzania. However, the potential challenges discussed need to be addressed in order to develop a sustainable national D&I research conference by incorporating recommendations that forum attendees proposed.

HPV Type Distribution in HIV Positive and Negative Women With or Without Cervical Dysplasia or Cancer in East Africa.

BACKGROUND: Women living with HIV in sub-Saharan Africa are at increased risk to develop cervical cancer (CC), which is caused by persistent infection with 13 oncogenic human papilloma viruses (HR-HPVs). It is important to accurately identify and target HIV-positive women at highest risk to develop CC for early therapeutic intervention. METHODS: A total of 2,134 HIV+ and HIV- women from South-West Tanzania were prospectively screened for cervical cancer and precancerous lesions. Women with cervical cancer (n=236), high- and low-grade squamous intraepithelial lesions (HSIL: n=68, LSIL: n=74), and without lesion (n=426) underwent high-resolution HPV genotyping. RESULTS: Eighty percent of women who were diagnosed with HSIL or LSIL were living with HIV. Any lesion, young age, HIV status, and depleted CD4 T cell counts were independent risk factors for HPV infections, which were predominantly caused by HR-HPV types. While multiple HR-HPV type infections were predominant in HIV+ women with HSIL, single-type infections predominated in HIV+ CC cases (p=0.0006). HPV16, 18, and 45 accounted for 85% (68/80) and 75% (82/110) of HIV+ and HIV- CC cases, respectively. Of note, HPV35, the most frequent HPV type in HSIL-positive women living with HIV, was rarely detected as a single-type infection in HSIL and cancer cases. CONCLUSION: HPV16, 18, and 45 should receive special attention for molecular diagnostic algorithms during CC prevention programs for HIV+ women from sub-Saharan Africa. HPV35 may have a high potential to induce HSIL in women living with HIV, but less potential to cause cervical cancer in single-type infections.

Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV.

Background: Cervical cancer - caused by persistent High Risk Human Papilloma Virus (HR HPV) infections - is the second most common cancer affecting women globally. HIV infection increases the risk for HPV persistence, associated disease progression and malignant cell transformation. We therefore hypothesized that this risk increase is directly linked to HIV infection associated dysfunction or depletion of HPV-oncoprotein-specific T-cell responses. Methods: The 2H study specifically included HIV+ and HIV- women with and without cervical lesions and cancer to analyze HPV oncogene-specific T cell responses in relation to HPV infection, cervical lesion status and HIV status. Oncoprotein E6 and E7 specific T-cell responses were quantified for the most relevant types HPV16, 18 and 45 and control antigens (CMV-pp65) and M.tb-PPD in 373 women, using fresh peripheral blood mononuclear cells in an IFN-γ release ELISpot assay. Results: Overall, systemic E6- and E7-oncoprotein-specific T-cell responses were infrequent and of low magnitude, when compared to CMV-pp65 and M.tb-PPD (p < 0.001 for all HR HPV types). Within HIV negative women infected with either HPV16, 18 or 45, HPV16 infected women had lowest frequency of autologous-type-E6/E7-specific T-cell responses (33%, 16/49), as compared to HPV18 (46% (6/13), p = 0.516) and HPV45 (69% (9/13), p = 0.026) infected women. Prevalent HPV18 and 45, but not HPV16 infections were linked to detectable oncoprotein-specific T-cell responses, and for these infections, HIV infection significantly diminished T-cell responses targeting the autologous infecting genotype. Within women living with HIV, low CD4 T-cell counts, detectable HIV viremia as well as cancerous and precancerous lesions were significantly associated with depletion of HPV oncoprotein-specific T-cell responses. Discussion: Depletion of HPV-oncoprotein-specific T-cell responses likely contributes to the increased risk for HR HPV persistence and associated cancerogenesis in women living with HIV. The low inherent immunogenicity of HPV16 oncoproteins may contribute to the exceptional potential for cancerogenesis associated with HPV16 infections.

Wuchereria bancrofti infection is linked to systemic activation of CD4 and CD8 T cells.

BACKGROUND: Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation. METHODOLOGY/PRINCIPAL FINDINGS: Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DRposCD38pos CD4 T cells and effector memory cells CD4 T cells (CD45ROposCD27neg) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections. CONCLUSIONS/SIGNIFICANCE: W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection.

Envelope-Specific Recognition Patterns of HIV Vaccine-Induced IgG Antibodies Are Linked to Immunogen Structure and Sequence.

Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines. Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 µg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition. Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG (p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group. Conclusions: IgG recognition of linear antigenic Env regions differed between the two trials particularly after the second MVA boost. Structural features of the MVA-encoded immunogens, such as secreted, monomeric gp120 vs. membrane-anchored, functional gp150, and differences in prime-boost immunogen sequence variability most probably contributed to these differences. Prime-boosting with multivalent Env immunogens during TMV01 did not improve variant cross-recognition of immunodominant peptide variants in the V3 region.

Accuracy and Operational Characteristics of Xpert Human Immunodeficiency Virus Point-of-Care Testing at Birth and Until Week 6 in Human Immunodeficiency Virus-exposed Neonates in Tanzania.

Background: Point-of-care (PoC) systems for early infant diagnosis (EID) may improve timely infant human immunodeficiency virus (HIV) management. Experiences within African public health settings are limited. Methods: We evaluated the accuracy and operational feasibility of the Xpert HIV-1 Qual for PoC-EID testing, using fresh blood and dried blood spots (DBS) samples at obstetric health facilities in Tanzania at birth and at postpartum weeks 1, 2, 3, and 6 in HIV-exposed infants. Test results were confirmed using TaqMan DBS HIV-deoxyribonucleic acid and/or plasma HIV-ribonucleic acid (RNA) testing. Results: At week 6, 15 (2.5%) out of 614 infants were diagnosed with HIV; 10 (66.7%) of them at birth (median HIV-RNA 4570 copies/mL). At birth, the Xpert-PoC and Xpert-DBS were 100% sensitive (95% confidence intervals: PoC, 69.2-100%; DBS, 66.4-100%) and 100% specific (PoC, 92.1-100%; DBS, 88.4-100%). By week 3, 5 infants with intra/postpartum HIV-infection (median HIV-RNA 1 160 000 copies/mL) were all correctly diagnosed by Xpert. In 2 cases, Xpert-PoC testing correctly identified HIV-infection when DBS tests (Xpert and TaqMan) were negative, suggesting a greater sensitivity. In 2 infants with confirmed HIV at birth, all tests were negative at week 6, possibly because of viral suppression under nevirapine prophylaxis. Problems were reported in 183/2736 (6.7%) of Xpert-PoC tests, mostly related to power cuts (57.9%). Conclusions: We demonstrated excellent Xpert HIV-1 Qual performance and good operational feasibility for PoC-EID testing at obstetric health facilities. Week 6 sensitivity issues were possibly related to nevirapine prophylaxis, supporting additional birth PoC-EID testing to avoid underdiagnosis. Clinical Trials Registration: NCT02545296.

Optimizing the immunogenicity of HIV prime-boost DNA-MVA-rgp140/GLA vaccines in a phase II randomized factorial trial design.

BACKGROUND: We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique. METHODS: Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL [6mg/mL] plus EP). Second the same volunteers received 108 pfu HIV-MVA twice, alone or combined with CN54rgp140/GLA-AF, intramuscularly by syringe, 16 weeks apart. Additionally, 20 volunteers received saline placebo. RESULTS: Vaccinations and electroporation did not raise safety concerns. After the last vaccination, the overall IFN-γ ELISpot response rate to either Gag or Env was 97%. Intradermal electroporation significantly increased ELISpot response rates to HIV-DNA-specific Gag (66% group I vs. 86% group II, p = 0.026), but not to the HIV-MVA vaccine-specific Gag or Env peptide pools nor the magnitude of responses. Co-administration of rgp140/GLA-AF with HIV-MVA did not impact the frequency of binding antibody responses against subtype B gp160, C gp140 or E gp120 antigens (95%, 99%, 79%, respectively), but significantly enhanced the magnitude against subtype B gp160 (2700 versus 300, p<0.001) and subtype C gp140 (24300 versus 2700, p<0.001) Env protein. At relatively low titers, neutralizing antibody responses using the TZM-bl assay were more frequent in vaccinees given adjuvanted protein boost. CONCLUSION: Intradermal electroporation increased DNA-induced Gag response rates but did not show an impact on Env-specific responses nor on the magnitude of responses. Co-administration of HIV-MVA with rgp140/GLA-AF significantly enhanced antibody responses.

Mate Yako Afya Yako: Formative research to develop the Tanzania HIV self-testing education and promotion (Tanzania STEP) project for men.

The purpose of this formative research, guided by the Integrated Behavioral Model, was to assess men's attitudes and personal agency towards HIV self-testing (HIVST) and confirmatory HIV testing in order to inform the development of the Tanzania STEP (Self-Testing Education and Promotion) Project, a peer-based HIV self-testing intervention for young men in Tanzania. Qualitative in-depth interviews were conducted with 23 men in Dar es Salaam, Tanzania who socialize in networks locally referred to as "camps". Men reported privacy, confidentiality, and saving time as the primary reasons for their self-testing interest. Most participants had high perceived control and self-efficacy to self-test and seek confirmatory HIV testing. Nevertheless, men reported concerns related to their ability to perform the test and the potential lack of post-test counseling. Specific recommendations for the intervention included providing HIVST education and pre-test counseling, and using mobile health (mHealth) strategies for participants to reach a healthcare professional for further assistance. The findings suggest that while HIVST is highly acceptable among men in Tanzania, future interventions will need to address the challenges that men may face with HIVST before promoting it as an alternative or supplement to facility-based HIV testing.

Reduction of malaria prevalence after introduction of artemisinin-combination-therapy in Mbeya Region, Tanzania: results from a cohort study with 6773 participants.

BACKGROUND: A marked decline in malaria morbidity and mortality has been reported after the introduction of artemisinin-based combination therapy (ACT) in high malaria prevalence countries in Africa. Data on the impact of ACT and on the prevalence of malaria has so far been scarce for Southwest Tanzania. METHODS: Between 2005 and 2011, a large general population cohort in the Mbeya Region in the south-west of Tanzania has been surveyed within the EMINI-study (Evaluation and Monitoring of the Impact of New Interventions). Participants were examined once per year, including rapid diagnostic testing for malaria. ACT was introduced in the region according to national guidelines in the time period 2006/2007, replacing sulfadoxine/pyrimethamine as first-line therapy. In four study sites, 6773 individuals who participated in the first two of three consecutive survey visits in the period from 2006 to 2009 were included in this analysis. The prevalence of Plasmodium infection prior to and after the introduction of ACT was compared by logistic regression, with consideration of climatic variability, age, sex, socio-economic status and bed net use as potential confounders. RESULTS: A significant reduction over time in the prevalence of Plasmodium falciparum infection from 2.5 to 0.3% was shown across the four study sites. The decline was not explained by other factors included in the analysis, therefore, the decline over time most likely reflects the impact of introduction of ACT in the study area. CONCLUSIONS: The longitudinal study showed a significant and relevant decline in the prevalence of P. falciparum infection after introduction of ACT, which could not be explained by potential confounders. The data suggests that artemisinin-based combinations are not only an effective instrument for reduction of immediate morbidity and mortality, but also for reduction of transmission rates.

Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost.

Background: We report the first-in-human safety and immunogenicity evaluation of PENNVAX-G DNA/modified vaccinia Ankara-Chiang Mai double recombinant (MVA-CMDR) prime-boost human immuonodeficiency virus (HIV) vaccine, with intramuscular DNA delivery by either Biojector 2000 needle-free injection system (Biojector) or CELLECTRA electroporation device. Methods: Healthy, HIV-uninfected adults were randomized to receive 4 mg of PENNVAX-G DNA delivered intramuscularly by Biojector or electroporation at baseline and week 4 followed by intramuscular injection of 108 plaque forming units of MVA-CMDR at weeks 12 and 24. The open-label part A was conducted in the United States, followed by a double-blind, placebo-controlled part B in East Africa. Solicited and unsolicited adverse events were recorded, and immune responses were measured. Results: Eighty-eight of 100 enrolled participants completed all study injections, which were generally safe and well tolerated, with more immediate, but transient, pain in the electroporation group. Cellular responses were observed in 57% of vaccine recipients tested and were CD4 predominant. High rates of binding antibody responses to CRF01_AE antigens, including gp70 V1V2 scaffold, were observed. Neutralizing antibodies were detected in a peripheral blood mononuclear cell assay, and moderate antibody-dependent, cell-mediated cytotoxicity activity was demonstrated. Discussion: The PVG/MVA-CMDR HIV-1 vaccine regimen is safe and immunogenic. Substantial differences in safety or immunogenicity between modes of DNA delivery were not observed. Clinical Trials Registration: NCT01260727.

Correction: Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.

[This corrects the article DOI: 10.1371/journal.ppat.1005742.].

Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine Regimen.

Prime-boost vaccination strategies against HIV-1 often include multiple variants for a given immunogen for better coverage of the extensive viral diversity. To study the immunologic effects of this approach, we characterized breadth, phenotype, function, and specificity of Gag-specific T cells induced by a DNA-prime modified vaccinia virus Ankara (MVA)-boost vaccination strategy, which uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding a subtype B and AB-recombinant Gagp37 and two vaccinations with MVA-CMDR encoding subtype A Gagp55 Gag-specific T-cell responses were studied in 42 vaccinees using fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost, vaccine-induced gamma interferon-positive (IFN-γ+) Gag-specific T-cell responses were dominated by CD4+ T cells (P < 0.001 compared to CD8+ T cells) that coexpressed interleukin-2 (IL-2) (66.4%) and/or tumor necrosis factor alpha (TNF-α) (63.7%). A median of 3 antigenic regions were targeted with a higher-magnitude median response to Gagp24 regions, more conserved between prime and boost, compared to those of regions within Gagp15 (not primed) and Gagp17 (less conserved; P < 0.0001 for both). Four regions within Gagp24 each were targeted by 45% to 74% of vaccinees upon restimulation with DNA-SMI-Gag matched peptides. The response rate to individual antigenic regions correlated with the sequence homology between the MVA- and DNA Gag-encoded immunogens (P = 0.04, r2 = 0.47). In summary, after the first MVA-CMDR boost, the sequence-mismatched DNA-prime MVA-boost vaccine strategy induced a Gag-specific T-cell response that was dominated by polyfunctional CD4+ T cells and that targeted multiple antigenic regions within the conserved Gagp24 protein.IMPORTANCE Genetic diversity is a major challenge for the design of vaccines against variable viruses. While including multiple variants for a given immunogen in prime-boost vaccination strategies is one approach that aims to improve coverage for global virus variants, the immunologic consequences of this strategy have been poorly defined so far. It is unclear whether inclusion of multiple variants in prime-boost vaccination strategies improves recognition of variant viruses by T cells and by which mechanisms this would be achieved, either by improved cross-recognition of multiple variants for a given antigenic region or through preferential targeting of antigenic regions more conserved between prime and boost. Engineering vaccines to induce adaptive immune responses that preferentially target conserved antigenic regions of viral vulnerability might facilitate better immune control after preventive and therapeutic vaccination for HIV and for other variable viruses.

Trichuris trichiura infection and its relation to environmental factors in Mbeya region, Tanzania: A cross-sectional, population-based study.

BACKGROUND: The intestinal nematode Trichuris trichiura is among the most common causes of human infectious disease worldwide. As for other soil-transmitted nematodes, its reproductive success and thus prevalence and intensity of infection in a given area strongly depend on environmental conditions. Characterization of the influence of environmental factors can therefore aid to identify infection hot spots for targeted mass treatment. METHODOLOGY: We analyzed data from a cross-sectional survey including 6234 participants from nine distinct study sites in Mbeya region, Tanzania. A geographic information system was used to combine remotely sensed and individual data, which were analyzed using uni- and multivariable Poisson regression. Household clustering was accounted for and when necessary, fractional polynomials were used to capture non-linear relationships between T. trichiura infection prevalence and environmental variables. PRINCIPAL FINDINGS: T. trichiura infection was restricted to the Kyela site, close to Lake Nyasa with only very few cases in the other eight sites. The prevalence of T. trichiura infection in Kyela was 26.6% (95% confidence interval (CI) 23.9 to 29.6%). Multivariable models revealed a positive association of infection with denser vegetation (prevalence ratio (PR) per 0.1 EVI units = 2.12, CI 1.28 to 3.50) and inverse associations with rainfall (PR per 100 mm = 0.54, CI 0.44 to 0.67) and elevation (PR per meter = 0.89, CI 0.86 to 0.93) while adjusting for age and previous worm treatment. Slope of the terrain was modelled non-linearly and also showed a positive association with T. trichiura infection (p-value p<0.001). CONCLUSION/SIGNIFICANCE: Higher prevalences of T. trichiura infection were only found in Kyela, a study site characterized by denser vegetation, high rainfall, low elevation and flat terrain. But even within this site, we found significant influences of vegetation density, rainfall, elevation and slope on T. trichiura infection. The inverse association of rainfall with infection in Kyela is likely due to the fact, that rainfall in this site is beyond the optimum conditions for egg development. Our findings demonstrate that use of remotely sensed environmental data can aid to predict high-risk areas for targeted helminth control.

Linkage into care among newly diagnosed HIV-positive individuals tested through outreach and facility-based HIV testing models in Mbeya, Tanzania: a prospective mixed-method cohort study.

OBJECTIVE: Linkage to care is the bridge between HIV testing and HIV treatment, care and support. In Tanzania, mobile testing aims to address historically low testing rates. Linkage to care was reported at 14% in 2009 and 28% in 2014. The study compares linkage to care of HIV-positive individuals tested at mobile/outreach versus public health facility-based services within the first 6 months of HIV diagnosis. SETTING: Rural communities in four districts of Mbeya Region, Tanzania. PARTICIPANTS: A total of 1012 newly diagnosed HIV-positive adults from 16 testing facilities were enrolled into a two-armed cohort and followed for 6 months between August 2014 and July 2015. 840 (83%) participants completed the study. MAIN OUTCOME MEASURES: We compared the ratios and time variance in linkage to care using the Kaplan-Meier estimator and Log rank tests. Cox proportional hazards regression models to evaluate factors associated with time variance in linkage. RESULTS: At the end of 6 months, 78% of all respondents had linked into care, with differences across testing models. 84% (CI 81% to 87%, n=512) of individuals tested at facility-based site were linked to care compared to 69% (CI 65% to 74%, n=281) of individuals tested at mobile/outreach. The median time to linkage was 1 day (IQR: 1-7.5) for facility-based site and 6 days (IQR: 3-11) for mobile/outreach sites. Participants tested at facility-based site were 78% more likely to link than those tested at mobile/outreach when other variables were controlled (AHR=1.78; 95% CI 1.52 to 2.07). HIV status disclosure to family/relatives was significantly associated with linkage to care (AHR=2.64; 95% CI 2.05 to 3.39). CONCLUSIONS: Linkage to care after testing HIV positive in rural Tanzania has increased markedly since 2014, across testing models. Individuals tested at facility-based sites linked in significantly higher proportion and modestly sooner than mobile/outreach tested individuals. Mobile/outreach testing models bring HIV testing services closer to people. Strategies to improve linkage from mobile/outreach models are needed.

HIV-1 Genetic Diversity Among Incident Infections in Mbeya, Tanzania.

In preparation for vaccine trials, HIV-1 genetic diversity was surveyed between 2002 and 2006 through the Cohort Development study in the form of a retrospective and prospective observational study in and around the town of Mbeya in Tanzania's Southwest Highlands. This study describes the molecular epidemiology of HIV-1 strains obtained from 97 out of 106 incident HIV-1 infections identified in three subpopulations of participants (one rural, two urban) from the Mbeya area. Near full-genome or half-genome sequencing showed a subtype distribution of 40% C, 17% A1, 1% D, and 42% inter-subtype recombinants. Compared to viral subtyping results previously obtained from the retrospective phase of this study, the overall proportion of incident viral strains did not change greatly during the study course, suggesting maturity of the epidemic. A comparison to a current Phase I-II vaccine being tested in Africa shows ∼17% amino acid sequence difference between the gp120 of the vaccine and subtype C incident strains. Phylogenetic and recombinant breakpoint analysis of the incident strains revealed the emergence of CRF41_CD and many unique recombinants, as well as the presence of six local transmission networks most of which were confined to the rural subpopulation. In the context of vaccine cohort selection, these results suggest distinct infection transmission dynamics within these three geographically close subpopulations. The diversity and genetic sequences of the HIV-1 strains obtained during this study will greatly contribute to the planning, immunogen selection, and analysis of vaccine-induced immune responses observed during HIV-1 vaccine trials in Tanzania and neighboring countries.

Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study.

BACKGROUND: The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania. METHODS: In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis. FINDINGS: Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly 18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1·91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0·80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2·17 (95% CI 1·08-4·37, p=0·0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors. INTERPRETATION: To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented. FUNDING: European Union as part of EuropAid; German Federal Ministry of Education and Research; German Center for Infection Research.

Correction: Prevalence of Lymphatic Filariasis and Treatment Effectiveness of Albendazole/ Ivermectin in Individuals with HIV Co-infection in Southwest-Tanzania.

[This corrects the article DOI: 10.1371/journal.pntd.0004618.].