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Vaccine-induced HIV antibodies were evaluated in serum samples collected from healthy Tanzanian volunteers participating in a phase I/II placebo-controlled double blind trial using multi-clade, multigene HIV-DNA priming and recombinant modified vaccinia Ankara (HIV-MVA) virus boosting (HIVIS03). The HIV-DNA vaccine contained plasmids expressing HIV-1 gp160 subtypes A, B, C, Rev B, Gag A, B and RTmut B, and the recombinant HIV-MVA boost expressed CRF01_AE HIV-1 Env subtype E and Gag-Pol subtype A. While no neutralizing antibodies were detected using pseudoviruses in the TZM-bl cell assay, this prime-boost vaccination induced neutralizing antibodies in 83% of HIVIS03 vaccinees when a peripheral blood mononuclear cell (PBMC) assay using luciferase reporter-infectious molecular clones (LucR-IMC) was employed. The serum neutralizing activity was significantly (but not completely) reduced upon depletion of natural killer (NK) cells from PBMC (p=0.006), indicating a role for antibody-mediated Fcγ-receptor function. High levels of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies against CRF01_AE and/or subtype B were subsequently demonstrated in 97% of the sera of vaccinees. The magnitude of ADCC-mediating antibodies against CM235 CRF01_AE IMC-infected cells correlated with neutralizing antibodies against CM235 in the IMC/PBMC assay. In conclusion, HIV-DNA priming, followed by two HIV-MVA boosts elicited potent ADCC responses in a high proportion of Tanzanian vaccinees. Our findings highlight the potential of HIV-DNA prime HIV-MVA boost vaccines for induction of functional antibody responses and suggest this vaccine regimen and ADCC studies as potentially important new avenues in HIV vaccine development. Trial Registration: Controlled-Trials The Pan African Clinical Trials Registry [ABSTRACT FROM AUTHOR]

Background: Volunteers in phase I/II HIV vaccine trials are assumed to be at low risk of acquiring HIV infection and are expected to have normal lives in the community. However, during participation in the trials, volunteers may encounter social harm and changes in their sexual behaviours. The current study aimed to study persistence of social harm and changes in sexual practices over time among phase I/II HIV vaccine immunogenicity (HIVIS03) trial volunteers in Dar es Salaam, Tanzania. Methods and Results: A descriptive prospective cohort study was conducted among 33 out of 60 volunteers of HIVIS03 trial in Dar es Salaam, Tanzania, who had received three HIV-1 DNA injections boosted with two HIV-1 MVA doses. A structured interview was administered to collect data. Analysis was carried out using SPSS and McNemars’ chi-square (χ2) was used to test the association within-subjects. Participants reported experiencing negative comments from their colleagues about the trial; but such comments were less severe during the second follow up visits (χ2 = 8.72; P<0.001). Most of the comments were associated with discrimination (χ2 = 26.72; P<0.001), stigma (χ2 = 6.06; P<0.05), and mistrust towards the HIV vaccine trial (χ2 = 4.9; P<0.05). Having a regular sexual partner other than spouse or cohabitant declined over the two follow-up periods (χ2 = 4.45; P<0.05). Conclusion: Participants in the phase I/II HIV vaccine trial were likely to face negative comments from relatives and colleagues after the end of the trial, but those comments decreased over time. In this study, the inherent sexual practice of having extra sexual partners other than spouse declined over time. Therefore, prolonged counselling and support appears important to minimize risky sexual behaviour among volunteers after participation in HIV Vaccine trials. [ABSTRACT FROM AUTHOR]

Background Eventual control of HIV/AIDS is believed to be ultimately dependent on a safe, effective and affordable vaccine. Participation of sub-Saharan Africa in the conduct of HIV trials is crucial as this region still experiences high HIV incidences. We describe the experience of recruiting and retaining volunteers in the first HIV vaccine trial (HIVIS03) in Tanzania. Methods In this trial enrolled volunteers from amongst Police Officers (POs) in Dar es Salaam were primed with HIV-1 DNA vaccine at months 0, 1 and 3; and boosted with HIV-1 MVA vaccine at months 9 and 21. A stepwise education provision/sensitization approach was employed to eventual recruitment. Having identified a "core" group of POs keen on HIV prevention activities, those interested to participate in the vaccine trial were invited for a first screening session that comprised of provision of detailed study information and medical evaluation. In the second screening session results of the initial assessment were provided and those eligible were assessed for willingness to participate (WTP). Those willing were consented and eventually randomized into the trial having met the eligibility criteria. Voluntary participation was emphasized throughout. Results Out of 408 POs who formed the core group, 364 (89.0%) attended the educational sessions. 263 out of 364 (72.2%) indicated willingness to participate in the HIV vaccine trial. 98% of those indicating WTP attended the pre-screening workshops. 220 (85.0%) indicated willingness to undergo first screening and 177 POs attended for initial screenings, of whom 162 (91.5%) underwent both clinical and laboratory screenings. 119 volunteers (73.5%) were eligible for the study. 79 were randomized into the trial, while 19 did not turn up, the major reason being partner/family advice. 60 volunteers including 15 females were recruited during a one-year period. All participated in the planned progress updates workshops. Retention into the schedule was: 98% for the 3 DNA/placebo vaccinations, while it was 83% and 73% for the first and second MVA/placebo vaccinations respectively. Conclusion In this first HIV vaccine trial in Tanzania, we successfully recruited the volunteers and there was no significant loss to follow up. Close contact and updates on study progress facilitated the observed retention rates. [ABSTRACT FROM AUTHOR]

Background: Recruitment, enrollment and retention of volunteers in an HIV vaccine trial is important in the efforts to ultimately develop a vaccine that can prevent new HIV infections. Following recruitment, some randomized individuals decline to be enrolled in an HIV vaccine trial. The reasons for such a decision are not well known. This article describes why individuals who were randomized in a phase I and II HIV vaccine trial in Dar es Salaam, Tanzania declined to be enrolled. Methods: Face-to-face interviews were conducted with 14 individuals (7 men and 7 women). Repeated readings of the 14 interview transcripts to look for reasons for declining to enroll in the trial were performed. Data was analyzed using the content analysis approach. Results: Informants expressed fear of the outcome of an experimental HIV vaccine in their lives. Unlike women, some men were concerned over the effect of the vaccine on their reproduction intentions. Women were concerned about the unknown effects of the vaccine in their bodies. Also, to a large extent, informants faced resistance from significant others such as fiancées, parents, relatives, and friends. Women were influenced by their potential intimate sexual partners; men were forbidden by their parents, and mothers had the most influential opinion. Conclusions: Fear of the negative outcome of an experimental vaccine and resistance from significant others are the main reasons for declining to enroll in the HIV vaccine trial among eligible volunteers after randomization. The resistance from the significant others provides valuable guidance for designing future trials in Tanzania; for example, expanding the HIV vaccine trial education to the general population from the onset of the trial design. [ABSTRACT FROM AUTHOR]

Background. A human immunodeficiency virus (HIV) vaccine that limits disease and transmission is urgently needed. This clinical trial evaluated the safety and immunogenicity of an HIV vaccine that combines a plasmid-DNA priming vaccine and a modified vaccinia virus Ankara (MVA) boosting vaccine. Methods. Forty healthy volunteers were injected with DNA plasmids containing gp160 of HIV-1 subtypes A, B, and C; rev B; p17/p24 gagAand B, and RTmut B by use of a needle-free injection system. The vaccine was administered intradermally or intramuscularly, with or without recombinant granulocyte macrophage colony-stimulating factor, and boosted with a heterologous MVA containing env, gag, and pol of CRF01A_E. Immune responses were monitored with HIV-specific interferon (IFN)-γ and interleukin (IL)-2 ELISpot and lymphoproliferative assays (LPAs). Results. Vaccine-related adverse events were mild and tolerable. After receipt of the DNA priming vaccine, 11 (30%) of 37 vaccinees had HIV-specific IFN-γ responses. After receipt of the MVA boosting vaccine, ELISpot assays showed that 34 (92%) of 37 vaccinees had HIV-specific IFN-γ responses, 32 (86%) to Gag and 24 (65%) to Env. IFN-γ production was detected in both the CD8+ T cell compartment (5 of 9 selected vaccinees) and the CD4+ T cell compartment (9 of 9). ELISpot results showed that 25 (68%) of 37 vaccinees had a positive IL-2 response and 35 (92%) of 38 had a positive LPA response. Of 38 subjects, a total of 37 (97%) were responders. One milligram of HIV-1 DNA administered intradermally was as effective as 4mg administered intramuscularly in priming for the MVA boosting vaccine. Conclusion. This HIV-DNA priming-MVA boosting approach is safe and highly immunogenic. Trials registration. International Standard Randomised Controlled Trial number: ISRCTN32604572. [ABSTRACT FROM AUTHOR]

Data on slow progression following HIV-1 infection in Africa are sparse. From a study on the natural history of HIV-1 infection in Dar es Salaam, Tanzania, an analysis of immunological and clinical data from 237 HIV-1 seropositive individuals was performed. Annual CD4 cell determinations were carried out by flow cytometry. None was on antiretroviral treatment. CD4+ cell slopes were obtained by fitting a linear regression model. A study population of 50 individuals with >3 CD4 cell determinations and followed for >5 y had a mean follow-up of 72.7 months, and mean 5.7 CD4+ cell determinations. With a criterion of maintaining a CD4 cell count ≥500 cells/µl, 8 of the 50 (16.0%) were long-term non-progressors (LTNP). With a definition of maintaining a CD4+ cell slope ≤ -10 (a loss of 10 or less cells per y), 13 (26.0%) were long-term slow progressors (LTSP). 11 of them (84.6%) had a baseline CD4 cell count <500 cells/µl and 5(38.5%) had a baseline CD4 cell count less than 350 cells/µl. An analysis of the selection bias introduced during slope determination is presented. With no selection, 24 (23.3%) would have documented slow CD4 progression among those enrolled for 5 or more y regardless of CD4 determinations. [ABSTRACT FROM AUTHOR]

Background: Syndromic management of STIs has been advocated as simplified and cheap approach. Youth have been reported to be at increased risk of acquiring STIs which can facilitate HIV transmission. We have investigated the relationship between the syndromic management and specific aetiology diagnosis and its relationship with HIV infection and health seeking behaviour among youth attending a reproductive health clinic in Dar es Salaam, Tanzania. Methods: Between September 1998 and February 1999 among 1895 adolescents and youth below 25 years seen in the clinic 199 (10.5%) were randomly selected and consented to participate in the study. A standard questionnaire was administered. Blood and vaginal or urethral specimens were taken and investigated for STI causative agents. Results: Among a total of 199 studied adolescents and youth 22.6 % were teenagers, with fewer females 17.8% than males; 27.5% (p < 0.018). 20.8% of the females compared to 11.5% in males were HIV infected. Genital discharge was the most common complaint which was reported in 54.1% of male and 63.4 % of female patients. All males with gonorrhoea and four out of five with Chlamydia were given appropriate treatment with syndromic management, while 28% women with gonorrhoea or Chlamydia received appropriate treatment by syndromic management. All patients found with active syphilis by serology had not complained of genital ulcers and would not have been assigned to syndromic treatment for syphilis at the initial visit. Conclusion: The burden of STIs in this youth population is large indicating that youth are at increased risk of STIs and will certainly require youth friendly clinics. There is a need to refine the current syndromic management guidelines. [ABSTRACT FROM AUTHOR]

Current HIV management guidelines are based on natural history studies from the developed world. Data on the similarity of the natural course of HIV-1 infection conflict with studies in the developing world. A cohort of 1887 hotel workers with no access to antiretroviral therapy was followed between 1990 and 1998 in Dar es Salaam through annual clinical evaluations and CD4 + T- lymphocyte (CD4 cell) count determinations. 196 (10.4%) were HIV-1 sero-prevalents; 133 (7.9%) were HIV-1 sero-incidents; and 1558 (82.6%) remained HIV seronegative. Follow-up duration was 13,719 and 82,742 months for HIV-1 seropositives and HIV seronegatives respectively. Clinical events occurred at median CD4 cell counts similar to those previously reported from the developed world, but death occurred at higher counts. Off-duty last 6 months, chronic diarrhoea and a faster CD4 cell count decline were associated with faster disease progression and death. In Tanzania HIV natural history is similar to that from the developed world and similar management guidelines could be employed. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the prevalence of HIV-1 infection, the clinical spectrum of HIV-1-associated conditions and HIV-1-associated mortality among children hospitalized in the medical paediatric wards at Muhimbili Medical Centre (MMC), Dar es Salaam, Tanzania. All children admitted to the medical paediatric wards of MMC between August 1995 and January 1996 were eligible for the study. Testing for HIV antibodies was done using 2 consecutive enzyme linked immunosorbent assays (ELISAs). ELISA-reactive samples from children aged 18 months and below were further tested by a recently developed heat-denatured p24 antigen assay. The prevalence of HIV-1 infection among the 2015 children studied was 19.2%. When present for 14 days or more, fever, cough, diarrhoea, ear discharge, oral ulcers and skin rash were all significantly more common in HIV-1-infected than in HIV-uninfected children (p < 0.001). In the multivariate analysis cough, ear discharge, oropharyngeal ulcers and skin rash were found to be the most important symptoms. Clinical signs found to be significantly associated with HIV-1 infection in the univariate analysis were wasting, stunting, hair changes, oral thrush, oropharyngeal ulcers, lymphadenopathy, lung consolidation and lung crepitations (p < 0.001). In the multivariate analysis, oral thrush, lung crepitations, cervical lymphadenopathy, wasting and inguinal lymphadenopathy were found to be the most important signs. The 3 most common diagnoses in HIV-1-infected children were acute respiratory infection (ARI) (39.4%), malnutrition (38.1%) and tuberculosis (19.3%), while in HIV-uninfected children they were malaria (47.0%), ARI (25.0%) and malnutrition (16.1%). The mortality rate was 21.4% in HIV-1-infected children and 8.4% in HIV-uninfected children (p < 0.001). In conclusion, the prevalence of HIV-1 infection among hospitalized children at the main hospital in Dar es Salaam was high and associated with high mortality. Many symptoms and signs are indicative of HIV-1 infection, but appropriate laboratory testing is required for diagnosis. [ABSTRACT FROM AUTHOR]

We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees. [ABSTRACT FROM AUTHOR]

Background: For more than three decades, Human Immunodeficiency Virus (HIV) infection and Acquired Immune Deficiency Syndrome (AIDS) continue to dominate the health agenda. In sub-Saharan African countries, women are at more risk of contracting HIV and AIDS compared with men due to biological, social, economic, socio-economic and cultural factors. Women in the uniformed services may be more vulnerable to HIV/AIDS because of their work context, mobility, age and other factors that expose them to a higher risk of infection than women in the general population. This article describes gender dimensions, motives and challenges towards HIV prevention amongst Police officers (POs) in Dar es Salaam, Tanzania.Methods: This was a descriptive qualitative study conducted at Police stations in Dar es Salaam, Tanzania. Fifteen in-depth interviews were conducted on POs; seven men, and eight women. Content analysis approach was used to analyze data.Results: Participants' self-descriptions shed light on gender differences in relation to self -perceptions, job contexts, sexual relationships and HIV prevention. Both men and women perceived themselves as role models, and believed that the surrounding community perceived the same. Safe sexual behavior appeared crucial to avoid undesirable health outcomes. Risky sexual practices were considered avoidable. Under unavoidable sexual temptations, women in particular would be keen to avoid risky sexual practices. Some participants expressed positive views towards condoms use during extra-marital sexual relationships, while others had negative opinions. Early phases of HIV vaccine trials appeared to gain support from sexual partners. However, condom use during phase I/II HIV vaccine trials was deemed as difficult. Support from the spouse was reported to influence condom use outside the wedlock. However, religious beliefs, socio-cultural issues and individual reasons were perceived as difficulties to promote condoms use.Conclusions: These findings increase understanding of gender differences and context specific efforts towards HIV prevention. Individuals' assertiveness against risky sexual practices and the intention to participate in HIV vaccine trials to develop an effective vaccine are worth noting. Nevertheless, uncertainties towards condoms use underscore the importance of condoms' marketing particularly in extra marital sexual relationships and during early HIV vaccine trials. [ABSTRACT FROM AUTHOR]

Background Short course antiretroviral (ARV) treatment around delivery reduces early mother-to-child transmission (MTCT) of HIV-1 by 35-60 %. However, additional interventions are required to prevent postnatal transmission through breastfeeding. We have performed two studies (MITRA and MITRA PLUS) to investigate the possibility to reduce MTCT of HIV-1 by prophylactic ARV treatment of infants or mothers during breastfeeding. Materials and methods In the MITRA study HIV-1 infected pregnant women were treated during late pregnancy and for one week after delivery with two ARV drugs, zidovudine (ZDV) and lamivudine (3TC). Infants were treated with these drugs for one week after birth and then with 3TC alone during breastfeeding (maximum 6 months). In the MITRA PLUS study the HIV-1 infected mothers were treated with three ARV drugs, ZDV+3TC+nevirapine (NVP) during late pregnancy and breastfeeding (NVP was replaced by nelfinavir for mothers with adverse reactions on NVP). Treatment of the mothers was stopped at six months except for those who needed ARV treatment for their own health. In both studies mothers were counseled on exclusive breastfeeding and encouraged to stop at six months. Transmission of HIV-1 was analyzed using the Kaplan Meier survival technique. Results In the MITRA study 398 infants were included in the transmission analysis. The cumulative proportion of HIVinfected infants was 3.8% (95%CI 2.0%-5.6%) at 6 weeks and 4.9% (95%CI 2.7%-7.1%) at 6 months of age. In the MITRA PLUS study there were 440 infants included in the transmission analysis. The proportion of HIV-1 infected infants was 4.1% (95%CI 2.1%-6.0%) at 6 weeks and 5.0% (95%CI 3.2%-7.0%) at 6 months. The median time of breastfeeding was 18 weeks in the MITRA study and 24 weeks in the MITRA PLUS study. NVP-related skin reactions occurred in 24 (5.5%) of 433 NVP-treated women, of whom 6 had Steven Johnson syndrome. All women with skin reactions had CD4 cell counts > 200/mm³. Conclusions The HIV-1 transmission rates at 6 weeks and 6 months after delivery in the MITRA and MITRA PLUS studies were similar and are among the lowest reported in a breastfeeding population in sub-Saharan Africa. The strategy used in the MITRA PLUS study is the obvious choice for mothers who need ARV treatment for their own health whereas prophylactic ARV treatment of the infant during breastfeeding could be a possible choice for mothers with high CD4 cell counts. [ABSTRACT FROM AUTHOR]

Background: Eventual control of HIV/AIDS is believed to be ultimately dependent on a safe, effective and affordable vaccine. Participation of sub-Saharan Africa in the conduct of HIV trials is crucial as this region still experiences high HIV incidences. We describe the experience of recruiting and retaining volunteers in the first HIV vaccine trial (HIVIS03) in Tanzania.Methods: In this trial enrolled volunteers from amongst Police Officers (POs) in Dar es Salaam were primed with HIV-1 DNA vaccine at months 0, 1 and 3; and boosted with HIV-1 MVA vaccine at months 9 and 21. A stepwise education provision/sensitization approach was employed to eventual recruitment. Having identified a "core" group of POs keen on HIV prevention activities, those interested to participate in the vaccine trial were invited for a first screening session that comprised of provision of detailed study information and medical evaluation. In the second screening session results of the initial assessment were provided and those eligible were assessed for willingness to participate (WTP). Those willing were consented and eventually randomized into the trial having met the eligibility criteria. Voluntary participation was emphasized throughout.Results: Out of 408 POs who formed the core group, 364 (89.0%) attended the educational sessions. 263 out of 364 (72.2%) indicated willingness to participate in the HIV vaccine trial. 98% of those indicating WTP attended the pre-screening workshops. 220 (85.0%) indicated willingness to undergo first screening and 177 POs attended for initial screenings, of whom 162 (91.5%) underwent both clinical and laboratory screenings. 119 volunteers (73.5%) were eligible for the study. 79 were randomized into the trial, while 19 did not turn up, the major reason being partner/family advice. 60 volunteers including 15 females were recruited during a one-year period. All participated in the planned progress updates workshops. Retention into the schedule was: 98% for the 3 DNA/placebo vaccinations, while it was 83% and 73% for the first and second MVA/placebo vaccinations respectively.Conclusion: In this first HIV vaccine trial in Tanzania, we successfully recruited the volunteers and there was no significant loss to follow up. Close contact and updates on study progress facilitated the observed retention rates.Trial Registration Numbers: ISRCTN90053831 ISRNCT01132976 and ATMR2009040001075080. [ABSTRACT FROM AUTHOR]