Early antiretroviral therapy and its impact on natural killer cell dynamics in HIV-1 infected men who have sex with men: a cross-sectional pilot study evaluating the impact of early ART initiation on NK cell perturbation in HIV infection.

Phenotypic changes and functional impairment of natural killer (NK) cells occur early in HIV-1 infection. Antiretroviral therapy (ART) effectively restores CD4+ T cell counts and suppresses HIV-1 to undetectable levels. The role and efficacy of immediate ART initiation in mitigating NK cell aberrations remain to be elucidated comprehensively. This study hypothesized that HIV-1 infection negatively influences NK cell evolution and that early ART initiation restores these perturbations. Blood samples were collected longitudinally from five acutely HIV-1 infected men who have sex with men in Nairobi, Kenya. Participants were immediately initiated on ART after HIV-1 diagnosis. Blood samples were drawn pre-infection and at sequential bi-weekly post-infection time points. Peripheral blood mononuclear cells were stained with panel NK cells surface markers to assess HIV-induced phenotypic changes by flow cytometry. Some cells were also stimulated overnight with K562 cell line, IL-2, and IL-15 and stained for flow cytometry functionality. HIV-1 infection was associated with significant reductions in the production of IFN-γ (P = 0.0264), expression of CD69 (P = 0.0110), and expression of NK cell inhibitory receptor Siglec7 (P = 0.0418). We observed an increased NK cell degranulation (P = 0.0100) and an upregulated expression of cell exhaustion marker PD-1 (P = 0.0513) at post-infection time points. These changes mainly were restored upon immediate initiation of ART, except for Siglec7 expression, whose reduced expression persisted despite ART. Some HIV-associated changes in NK cells may persist despite the immediate initiation of ART in acute HIV-1 infections. Our findings suggest that understanding NK cell dynamics and their restoration after ART can offer insights into optimizing HIV-1 treatment and potentially slowing disease progression.IMPORTANCENatural killer (NK) cells play a crucial role in controlling of HIV-1 replication and progression to disease. Perturbations of their functionality may therefore result in deleterious disease outcomes. Previous studies have demonstrated reduced NK cell functionality in chronic HIV-1 infection that positively correlated to HIV-1 viral load. This may suggest that control of HIV-1 viremia in acute HIV-1 infection may aid in enhancing NK cell response boosting the inate immunity hence effective control of viral spread and establishment of viral reservoir. Antiretroviral therapy (ART) effectively supresses HIV-1 viremia to undectable levels and restores CD4+ T cell counts. Our study highlights the significant role of early ART initiation in mitigating NK cell disruptions caused by acute HIV-1 infection. Our results suggest that early initiation of ART could have benefits beyond suppressing viral load and restoring CD4+ T cell counts. In addition, it could boost the innate immunity necessary to control disease progression.

Accelerating HIV vaccine development through meaningful engagement of local scientists and communities.

PURPOSE OF REVIEW: There is a need to conduct multiple experimental medicine trials in regions with significant burden of disease to ensure the global relevance of vaccines under development including the African context. RECENT FINDINGS: African scientists can support accelerated HIV vaccine development by leading EMVTs in the region in a complementary fashion to global efforts and augment evidence generated to optimize and advance relevant vaccines towards licensure. The ADVANCE program enables EMVTs, where local scientists lead trial implementation and immunogenicity endpoint analysis of promising vaccine approaches. Concerted efforts towards scientific collaboration, enhancing specific clinical and lab capacity, and improving ethical and regulatory systems to review EMVTs in Africa will be catalytic. Appropriate engagement of local communities and stakeholders will be equally important, and the field needs to refine existing research literacy approaches to effectively partner with communities around current complex scientific approaches. Review of inclusion of relevant populations in early research is also needed. SUMMARY: African scientists and communities can help accelerate HIV vaccine development through stronger global collaboration. Now is the time for bold investments to enable the conduct of innovative EMVTs in Africa where the eventual vaccines will have the greatest impact.

Improving access to maternal health services among rural hard-to-reach fishing communities in Uganda, the role of community health workers.

OBJECTIVES: To explore whether community health worker household-based maternal health visits improve antenatal care and skilled birth attendance among hard-to-reach fishing villages on Lake Victoria, Uganda. METHODS: This quasi-experimental 18-month prospective study involved 486 consenting women aged 15-49 years, who were pregnant or had a pregnancy outcome in the past 6 months, from 6 island fishing communities. The community health worker household-based intervention (community health workers' household visits to provide counseling, blood pressure measurement, anemia, and HIV testing) involved 243 women from three fishing communities. Random effects logistic regression was used to determine the association between the community health worker intervention and antenatal care and skilled birth attendance among women who had at least 5 months of pregnancy or childbirth at follow-up. RESULTS: Almost all women accepted the community health worker intervention (90.9% (221/243)). Hypertension was at 12.5% (27/216) among those who accepted blood pressure measurements, a third (33.3% (9/27)) were pregnant. HIV prevalence was 23.5% (52/221). Over a third (34.2% (69/202)) of women tested had anemia (hemoglobin levels less than 11 g/dL). The community health worker intervention was associated with attendance of first antenatal care visit within 20 weeks of pregnancy (adjusted odd ratio = 2.1 (95% confidence interval 0.6-7.6)), attendance of at least four antenatal care visits (adjusted odd ratio = 0.9 (95% confidence interval 0.4-2.0)), and skilled birth attendance (adjusted odd ratio = 0.5 (95% confidence interval 0.1-1.5)), though not statistically significant. CONCLUSION: Community health workers have a crucial role in improving early antenatal care attendance, early community-based diagnosis of anemia, hypertensive disorders, and HIV among women in these hard-to-reach fishing communities.

Oral pre-exposure prophylaxis preference, uptake, adherence and continuation among adolescent girls and young women in Kampala, Uganda: a prospective cohort study.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) has been scaled up; however, data from real-world settings are limited. We studied oral PrEP preference, uptake, adherence and continuation among adolescent girls and young women (AGYW) vulnerable to HIV in sub-Saharan Africa. METHODS: We conducted a prospective cohort study among 14- to 24-year-old AGYW without HIV who were followed for 12 months in Kampala, Uganda. Within at least 14 days of enrolment, they received two education sessions, including demonstrations on five biomedical interventions that are; available (oral PrEP), will be available soon (long-acting injectable PrEP and anti-retroviral vaginal ring) and in development (PrEP implant and HIV vaccine). Information included mode and frequency of delivery, potential side effects and method availability. Volunteers ranked interventions, 1 = most preferred to 5 = least preferred. Oral PrEP was "preferred" if ranked among the top two choices. All were offered oral PrEP, and determinants of uptake assessed using Poisson regression with robust error variance. Adherence was assessed using plasma tenofovir levels and self-reports. RESULTS: Between January and October 2019, 532 volunteers were screened; 285 enrolled of whom 265 received two education sessions. Mean age was 20 years (SD±2.2), 92.8% reported paid sex, 20.4% reported ≥10 sexual partners in the past 3 months, 38.5% used hormonal contraceptives, 26.9% had chlamydia, gonorrhoea and/or active syphilis. Of 265 volunteers, 47.6% preferred oral PrEP. Willingness to take PrEP was 90.2%; however, uptake was 30.6% (n = 81). Following enrolment, 51.9% started PrEP on day 14 (same day PrEP offered), 20.9% within 30 days and 27.2% after 30 days. PrEP uptake was associated with more sexual partners in the past 3 months: 2-9 partners (aRR = 2.36, 95% CI: 1.20-4.63) and ≥10 partners (aRR 4.70, 95% CI 2.41-9.17); oral PrEP preference (aRR 1.53, 95% CI 1.08-2.19) and being separated (aRR 1.55, 95% CI 1.04-2.33). Of 100 samples from 49 volunteers during follow up, 19 had quantifiable tenofovir levels (>10 µg/L) of which only three were protective (>40 µg/L). CONCLUSIONS: Half of AGYW preferred oral PrEP, uptake and adherence were low, uptake was associated with sexual behavioural risk and oral PrEP preference. Development of alternative biomedical products should be expedited to meet end-user preferences and, community delivery promoted during restricted movement.

Low awareness of oral and injectable PrEP among high-risk adolescent girls and young women in Kampala, Uganda.

BACKGROUND: Adolescent girls and young women (AGYW) account for a disproportionate number of new HIV infections worldwide. HIV prevalence among young sex workers in Uganda is 22.5%. Although pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention method, awareness of PrEP among AGYW in Uganda has not been studied systematically. We aimed to assess awareness of PrEP and factors associated with awareness of PrEP among AGYW who frequently reported paid sex. METHODS: We conducted a cross-sectional study among 14-24-year old AGYW at high risk of HIV infection in Kampala, Uganda from January to October 2019. Participants were screened for PrEP eligibility using a national screening tool of whom 82.3% were eligible. Data on socio-demographics, behavioral and sexual risks were collected by interview. Awareness of oral or injectable PrEP, the latter of which is currently in late-stage trials, was defined as whether an individual had heard about PrEP as an HIV prevention method. Multivariable robust poisson regression model was used to assess factors associated with oral PrEP awareness. RESULTS: We enrolled 285 participants of whom 39.3% were under 20 years old, 54.7% had completed secondary education, 68.8% had multiple sex partners in the past 3 months, 8.8% were screened as high risk drinkers'/ alcohol dependent (AUDIT tool) and 21.0% reported sex work as main occupation. Only 23.2% were aware of oral PrEP and 3.9% had heard about injectable PrEP. The prevalence of oral PrEP awareness was significantly higher among volunteers screened as alcohol dependents (aPR 1.89, 95% CI 1.08-3.29) and those with multiple sexual partners (aPR 1.84, 95% CI 1.01-3.35), but was lower among those who reported consistent condom use with recent sexual partners (aPR 0.58, 95% CI 0.37-0.91). CONCLUSIONS: Majority of AGYW were not aware of any kind of PrEP. Those with higher risk behavior, i.e. alcohol dependents or multiple sexual partners, were more aware of oral PrEP. Interventions to increase awareness among female youth are needed. Improving PrEP awareness is critical to increasing PrEP uptake among high-risk AGYW in Uganda.

Evaluating the effectiveness of enhanced family planning education on knowledge and use of family planning in fishing communities of Lake Victoria in Uganda: a randomized controlled trial.

INTRODUCTION: Family planning knowledge is poor and use is low in Ugandan fishing communities. We compared the effectiveness of enhanced family planning (FP) education with routine counselling on FP knowledge and use. METHODS: Individuals aged 15-49 years were randomly assigned to intervention or control arm. The intervention constituted enhanced FP education based on a simplified handout extracted from the WHO FP guidance tool called, "Family planning: A global handbook for FP providers" which participants took home for additional reading. The control arm constituted FP counselling following Uganda Ministry of Health guidelines. FP knowledge score and contraceptive prevalence rate (CPR) were compared between trial arms at baseline and at 12 months. Negative binomial regression models were used to estimate the effect of the intervention on FP knowledge and use. RESULTS: Overall, 1410 participants were screened to enrol 1004 (502 per study arm, 48.5% women). Subsequently, 384 (76.5%) and 383 (76.3%) completed the 12 months' follow-up in the intervention and control arms respectively. At baseline, a median FP knowledge score of 8 and a < 70% FP knowledge score was observed for all participants with a CPR of 36.8%. At month-12, the median FP knowledge score improved in both arms, higher in the intervention arm than the control arm (46 vs 30; p < 0.001). In the intervention arm, 304 (79.2%) had a score of ≥70 compared with 21 (5.5%) in the control arm (p < 0.001). In the negative binomial regression model, the change in FP knowledge score was 47% higher in the intervention arm than in the control arm (score ratio: 1.47, 95%CI: 1. 43-1.51, p < 0.001). The change in CPR was 16% higher in the intervention arm than in the control arm (Prevalence ratio: 1.16, 95%CI: 1.01-1.34, p < 0.040). INTERPRETATION: Enhanced FP education using a simplified FP education handout was more effective in increasing FP knowledge and use compared to routine FP counselling for people living in fishing communities. Innovative FP education interventions are recommended for improving FP knowledge and optimizing uptake in remote-rural settings where literacy levels are low. TRIAL REGISTRATION: The study was registered by the Pan African Clinical Trial Registry on 03 July 2021 with a Trial Registration Number PACTR202107891858045 . "Retrospectively registered".

Mobility for maternal health among women in hard-to-reach fishing communities on Lake Victoria, Uganda; a community-based cross-sectional survey.

BACKGROUND: Maternal mortality is still a challenge in Uganda, at 336 deaths per 100,000 live births, especially in rural hard to reach communities. Distance to a health facility influences maternal deaths. We explored women's mobility for maternal health, distances travelled for antenatal care (ANC) and childbirth among hard-to-reach Lake Victoria islands fishing communities (FCs) of Kalangala district, Uganda. METHODS: A cross sectional survey among 450 consenting women aged 15-49 years, with a prior childbirth was conducted in 6 islands FCs, during January-May 2018. Data was collected on socio-demographics, ANC, birth attendance, and distances travelled from residence to ANC or childbirth during the most recent childbirth. Regression modeling was used to determine factors associated with over 5 km travel distance and mobility for childbirth. RESULTS: The majority of women were residing in communities with a government (public) health facility [84.2 %, (379/450)]. Most ANC was at facilities within 5 km distance [72 %, (157/218)], while most women had travelled outside their communities for childbirth [58.9 %, (265/450)]. The longest distance travelled was 257.5 km for ANC and 426 km for childbirth attendance. Travel of over 5 km for childbirth was associated with adolescent girls and young women (AGYW) [AOR = 1.9, 95 % CI (1.1-3.6)], up to five years residency duration [AOR = 1.8, 95 % CI (1.0-3.3)], and absence of a public health facility in the community [AOR = 6.1, 95 % CI (1.4-27.1)]. Women who had stayed in the communities for up to 5 years [AOR = 3.0, 95 % CI (1.3-6.7)], those whose partners had completed at least eight years of formal education [AOR = 2.2, 95 % CI (1.0-4.7)], and those with up to one lifetime birth [AOR = 6.0, 95 % CI (2.0-18.1)] were likely to have moved to away from their communities for childbirth. CONCLUSIONS: Despite most women who attended ANC doing so within their communities, we observed that majority chose to give birth outside their communities. Longer travel distances were more likely among AGYW, among shorter term community residents and where public health facilities were absent. TRIAL REGISTRATION: PACTR201903906459874 (Retrospectively registered). https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=5977 .

Abortion and its correlates among female fisherfolk along Lake Victoria in Uganda.

INTRODUCTION: In Uganda, people living in fishing communities tend to engage in high-risk sexual activity which leads to unintended pregnancies that may end in abortions. Abortion has negative social, psychological, and medical impacts. We determined the frequency of abortion and its correlates among female fisher-folk along Lake Victoria in Uganda. METHODS: A cross-sectional survey was conducted among women aged 15- 49 years from Kigungu and Nsazi fishing communities. Data were collected on socio-demographic characteristics, abortion, and family planning use. Associations between abortion and participant characteristics were assessed using logistic regression models. RESULTS: Of the 713 women interviewed, 36, 5% were pregnant and 247, 34.6 % were using contraception. Majority (600, 84.2%) of those interviewed reported ever being pregnant. Approximately 45% of the pregnancies were un-intended while a third of those who had ever been pregnant (195, 32.5%) reported having aborted before. Slightly over a third (247, 34.6%) reported currently using or ever using family planning. Women aged 30+ years were more likely to abort compared to those aged 15-29 years (aOR: 2.7; 95% CI: 1.23-5.91). Women who had living children were less likely to abort compared to those who didn't have any living child (aOR: 0.06; 95% CI: 0.01 - 0.17). CONCLUSION: The rate of abortion among female fisher-folk in Uganda is substantial. Family planning use is still low and unintended pregnancies are common. Abortion risk increased with the age of the mother. Continuous behavioral change communication and optimization of family planning use are recommended to reduce abortions.

Correlates of knowledge of family planning among people living in fishing communities of Lake Victoria, Uganda.

BACKGROUND: Knowledge of family planning (FP) is a key determinant of contraceptive use which ultimately plays a role in attainment of good health and in conduct of clinical research. People living in fishing communities (FCs) have limited access to health services including FP and are targeted for future clinical research but their knowledge of FP and its correlates are scantily known. We determined correlates of knowledge of FP among people living in FCs of L. victoria in Uganda to inform future FP education programs in FCs. METHODS: We conducted a comparative cross-sectional survey among participants aged 15-49 years from Kigungu and Nsazi. Participants were asked if they were aware of any FP method. All those who responded in the affirmative were further asked to mention what FP methods they had heard of or knew. Those who reported knowledge of at least one FP method were asked a series of questions about FP methods and their side effects. Knowledge was categorized into good or poor knowledge based on their mean total score. Poor knowledge constituted a score below the mean while good knowledge constituted a score of more than or equal to the mean total score. To further explore attitudes and perceptions of FP, ten in-depth interviews and four focus group discussions were conducted. RESULTS: Of the 1410 screened participants, 94.5% were aware of at least one FP method. Pills and injectable hormonal methods were the most commonly known methods. Slightly over a third (38%) had good knowledge of FP. Correlates of knowledge of FP were; being female (aOR: 1.92 95% CI: 1.39-2.67), residing in Kigungu (aOR: 4.01 95% CI: 2.77-5.81), being married (aOR: 1.59 95% CI: 1.11-2.28) and currently being in a sexual relationship (aOR: 1.75 95% CI: 1.18-2.60). Concerns about safety and effectiveness of some modern FP methods exist. Misconceptions on effects of FP like sterility, cancers and foetal abnormalities were common. CONCLUSION: FP awareness among people living in FCs of L. Victoria in Uganda is high. However, good knowledge about specific methods tends to be low. Correlates of knowledge of FP include gender, residence, marital status and sexual engagement.

Components of antenatal care received by women in fishing communities on Lake Victoria, Uganda; a cross sectional survey.

BACKGROUND: Uganda has one of the highest maternal deaths at a ratio of 336 per 100,000 live births. As Uganda strives to achieve sustainable development goals, appropriate antenatal care is key to reduction of maternal mortality. We explored women's reported receipt of seven of the Uganda guidelines components of antenatal care, and associated factors in hard to reach Lake Victoria island fishing communities of Kalangala district. METHODS: A cross sectional survey among 486 consenting women aged 15-49 years, who were pregnant at any time in the past 6 months was conducted in 6 island fishing communities of Kalangala district, Uganda, during January-May 2018. Interviewer administered questionnaires, were used to collect data on socio-demographics and receipt of seven of the Uganda guidelines components of antenatal care. Regression modeling was used to determine factors associated with receipt of all seven components. RESULTS: Over three fifths (65.0%) had at least one ANC visit during current or most recent pregnancy. Fewer than a quarter of women who reported attending care at least four times received all seven ANC components [(23.6%), P < 0.05]. Women who reported receipt of ANC from the mainland were twice as likely to have received all seven components as those who received care from islands (aOR = 1.8; 95% CI:0.9-3.7). Receipt of care from a doctor was associated with thrice likelihood of receiving all components relative to ANC by a midwife or nurse (aOR = 3.2; 95% CI:1.1-9.1). CONCLUSIONS: We observed that the delivery of antenatal care components per Ugandan guidelines is poor in these communities. Cost effective endeavors to improve components of antenatal care received by women are urgently needed. Task shifting some components of ANC to community health workers may improve care in these island communities. TRIAL REGISTRATION: PACTR201903906459874 (Retrospectively registered).

Barriers and Facilitators of Family Planning Use in Fishing Communities of Lake Victoria in Uganda.

Introduction: Family planning (FP) is a key element in the conduct of research and is essential in managing family sizes. Although fishing communities (FCs) are targeted populations for HIV prevention research, their FP practices are poorly understood. We explored barriers and facilitators of FP use in FCs of Lake Victoria in Uganda. Methods: We employed a mixed-methods approach comprising a cross-sectional survey, in-depth interviews, and focus group discussions in 2 FCs. Multivariable logistic regression was used to analyze quantitative data and a thematic approach to generate themes from the qualitative data. Results: Up to 1410 individuals participated in the survey and 47 in the qualitative study. Just over a third (35.6%) used FP. The most commonly used methods were condoms, pills, and injectables. In Kigungu community, participants whose religion was Anglican and Muslim were more likely to use FP than Catholics (adjusted odds ratio [aOR] 1.45; 95% CI 1.05-1.99 and aOR 1.45; 95% CI 1.05-2.07, respectively). Participants were more likely to use FP if they had satisfactory FP knowledge compared to those with no satisfactory FP knowledge (aOR 1.79; 95% CI 1.23-2.61), or if they were married compared to their single counterparts (aOR 1.84; 95% CI 1.32-2.57). In both communities, participants were more likely to use FP if they had 2 or more sexual partners in the past 12 months than those with less than 2 sexual partners (aOR 1.41 95% CI 1.07-1.87 and aOR 2.60; 95% CI 1.36-4.97). Excessive bleeding and delayed fecundity; fertility desire; gender preferences of children; method stock outs and lack of FP trained personnel constituted barriers to FP use. There were also cultural influences in favor of large families. Conclusion: FP use in FCs is suboptimal. Barriers of FP use were mainly biomedical, religious, social, and cultural, which underscores a need for FP education and strengthening of FP service provision in FCs.

Prevalence and correlates of HIV infection among adolescents and young people living in fishing populations along Lake Victoria Fishing Communities in Uganda.

INTRODUCTION: fishing communities in Uganda are key populations for HIV, with persistently higher prevalence and incidence than the general population. METHODS: between March and August 2014, a cross sectional survey was conducted in 10 fishing communities of Lake Victoria in Uganda. Data was collected on socio-behavioural characteristics using interviewer administered questionnaires and venous blood collected for HIV testing. Prevalent HIV infections among adolescents and young people aged 13 to 24 years was estimated and the factors associated with those infections determined using multi variable logistic regression modelling. RESULTS: HIV prevalence was 10.8% among the 630 (96.5%) who provided a blood sample. Females were 3.5 times as likely to have HIV infection as males (aOR=3.52, 95% CI: 1.34-9.22). Young people aged 20-24 years were twice as likely to be HIV infected as those aged 13-19 years (aOR=1.77, 95% CI: 0.05-2.10), participants without formal education or those who had studied up to primary level were more likely to be HIV infected than those who had post primary education ((aOR=2.45, 95% CI: 1.19-5.07) or (5.29 (1.35-20.71) respectively). Reporting more than one sexual partner in the past 6 months was associated with HIV prevalent infection than those reporting no sexual partners (aOR=6.44, 95% CI: 1.27-32.83). CONCLUSION: adolescents and young people aged 13-24 years in fishing communities around Lake Victoria, Uganda, have a high HIV prevalence, with females having a three-fold higher level than males. These findings highlight-the need to improve HIV prevention among young females living in these fishing communities.

HIV immunoprophylaxis: preparing the pathway from proof of concept to policy decision and use.

Various long-awaited efficacy studies of vaccines and broadly neutralising antibodies for prevention of HIV are now well underway in highly endemic settings. One broadly neutralising monoclonal antibody is being assessed for proof of concept, and combinations are in the pipeline. Two multicomponent prime-and-boost vaccine regimens are being evaluated, one of which is designed for global coverage. These multicomponent vaccines present a new level of complexity that will challenge health delivery systems. We recommend that while awaiting the results, which will appear in 2020-22, the target product profiles and full public value proposition for both categories of products should be defined, and the regulatory, policy, and implementation pathways should be prepared. Economic and health benefits, cost of goods, administrative complexity, and user perspectives will be key considerations for the roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale-up. We propose a prioritisation of activities on the basis of a broad stakeholder consultation organised by WHO and UNAIDS.

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19).

BACKGROUND: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 µg) or low-dose (50 µg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. FINDINGS: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. INTERPRETATION: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). FUNDING: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.

Broad HIV-1 inhibition in vitro by vaccine-elicited CD8(+) T cells in African adults.

We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8(+) T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.

Acceptability and feasibility of repeated mucosal specimen collection in clinical trial participants in Kenya.

BACKGROUND: Mucosal specimens are essential to evaluate compartmentalized immune responses to HIV vaccine candidates and other mucosally targeted investigational products. We studied the acceptability and feasibility of repeated mucosal sampling in East African clinical trial participants at low risk of HIV and other sexually transmitted infections. METHODS AND FINDINGS: The Kenya AIDS Vaccine Initiative (KAVI) enrolled participants into three Phase 1 trials of preventive HIV candidate vaccines in 2011-2012 at two clinical research centers in Nairobi. After informed consent to a mucosal sub-study, participants were asked to undergo collection of mucosal secretions (saliva, oral fluids, semen, cervico-vaginal and rectal), but could opt out of any collection at any visit. Specimens were collected at baseline and two additional time points. A tolerability questionnaire was administered at the final sub-study visit. Of 105 trial participants, 27 of 34 women (79%) and 62 of 71 men (87%) enrolled in the mucosal sub-study. Nearly all sub-study participants gave saliva and oral fluids at all visits. Semen was collected from about half the participating men (47-48%) at all visits. Cervico-vaginal secretions were collected by Softcup from about two thirds of women (63%) at baseline, increasing to 78% at the following visits, with similar numbers for cervical secretion collection by Merocel sponge; about half of women (52%) gave cervico-vaginal samples at all visits. Rectal secretions were collected with Merocel sponge from about a quarter of both men and women (24%) at all 3 visits, with 16% of men and 19% of women giving rectal samples at all visits. CONCLUSIONS: Repeated mucosal sampling in clinical trial participants in Kenya is feasible, with a good proportion of participants consenting to most sampling methods with the exception of rectal samples. Experienced staff members of both sexes and trained counselors with standardized messaging may improve acceptance of rectal sampling.