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Background From 2019 to 2021, Rwandan residents of the border with the Democratic Republic of the Congo were offered the Ad26.ZEBOV (adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein) and MVA-BN-Filo (modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and nucleoprotein from Tai Forest viruses) Ebola vaccine regimen. Methods Nonpregnant persons aged ≥2 years were eligible. Unsolicited adverse events (UAEs) were reported through phone calls or visits, and serious adverse events (SAEs) were recorded per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Results Following Ad26.ZEBOV, UAEs were reported by 0.68% of 216 113 vaccinees and were more common in younger children (aged 2–8 years, 1.2%) compared with older children (aged 9–17 years, 0.4%) and adults (aged ≥18 years, 0.7%). Fever and headache were the most reported symptoms. All 17 SAEs related to vaccine were in children aged 2–8 years (10 postvaccination febrile convulsions ± gastroenteritis and 7 fever and/or gastroenteritis). The incidence of febrile seizures was 8 of 26 062 (0.031%) prior to initiation of routine acetaminophen in December 2020 and 2 of 15 897 (0.013%) thereafter. Nonobstetric SAEs were similar in males and females. All 20 deaths were unrelated to vaccination. Young girls and adult women with UAEs were less likely to receive the second dose than those without UAEs. Seven unrelated SAEs occurred in 203 267 MVA-BN-Filo recipients. Conclusions Postvaccination febrile convulsions in young children were rare but not previously described after Ad26.ZEBOV and were reduced with routine acetaminophen. The regimen was otherwise safe and well-tolerated.

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load., A single dose of a broadly neutralizing, HIV-specific antibody transiently reduces viral load in plasma, and in some individuals is associated with durable virus suppression in the absence of antiretroviral therapy.

Background Risks to mother and fetus following Ebola virus infection are very high. Evaluation of safety and immunogenicity of non-replicating Ebola vaccine candidates is a priority for use in pregnant women. This is the protocol for a randomized, open-label, single-center phase 3 clinical trial of the safety, reactogenicity, and immunogenicity of the 2-dose Ebola vaccine regimen in healthy adult pregnant women. This 2-dose regimen has been shown to be safe, judged effective, and approved in non-pregnant populations. Methods A total of 2000 adult (≥ 18 years of age) pregnant women will be enrolled from antenatal care facilities in Western Rwanda and randomized (1:1) to receive the 2-dose Ebola vaccine regimen (Ad26.ZEBOV, MVA-BN-Filo (group A)) or control (unvaccinated pregnant women (group B)). The primary objectives are to (1) assess adverse maternal/fetal outcomes in randomized pregnant women up to 1.5 months after delivery and (2) assess adverse neonatal/infant outcomes in neonates/infants born to randomized women up to 3.5 months after birth. The frequency and relatedness of all serious adverse events in women and newborns from randomization or birth, respectively, until study end will be reported. The reactogenicity and unsolicited adverse events of the 2-dose Ebola vaccine regimen in all vaccinated pregnant women (group A) will be reported. We will also assess the immunogenicity of the 2-dose Ebola vaccine regimen in 150 pregnant women who are anticipated to receive both vaccine doses within the course of their pregnancy (a subset of the 1000 pregnant vaccinated women from group A) compared to 150 non-pregnant women vaccinated after delivery (a subset of group B). The persistence of maternal antibodies in 75 infants born to women from the group A subset will be assessed. Exploratory analyses include assessment of acceptability of the 2-dose Ebola vaccine regimen among group A and assessment of maternal antibodies in breast milk in 50 women from group A and 10 controls (women from group B prior to vaccination). Discussion This study is intended to support a label variation to relax restrictions on use in pregnant women, a vulnerable population with high medical need. Trial registration Clinicaltrials.gov NCT04556526. September 21, 2020.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.

IntroductionIntramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants.MethodsForty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally.ResultsAll 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection.ConclusionRepeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989.

Background: A preventive vaccine for HIV is a critical public health need. Adeno-associated virus (AAV) mediated antibody gene delivery could be an alternative to immunization to induce sustained expression of neutralizing antibodies to prevent HIV. We conducted a first-in-human, phase 1 study of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralizing antibody against HIV. Methods: The trial was a phase 1, randomized, blinded, placebo-controlled, dose-escalation study at a single center in the UK. Healthy, HIV-uninfected men aged 18-45 were randomly assigned (3:1) to intervention or control in one of four dose-escalating cohorts (4x1012 vector genomes(vg), 4x1013 vg, 8x1013 vg or 1·2x1014 vg). Volunteers received intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps and were followed for 48 weeks. The primary objective was safety and tolerability. A secondary objective was to evaluate PG9 expression in serum and related HIV neutralization activity. This trial is registered with ClinicalTrials.gov, number NCT01937455. Findings: 21 volunteers were enrolled between February 10, 2014 and February 28, 2017 and completed 48 weeks follow-up. Reactogenicity was generally mild or moderate and self-limited. There were no probably or definitely related adverse events and no serious adverse events. We detected PG9 by HIV neutralization in serum of four volunteers, and by RT-PCR in muscle biopsies of four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in 10 volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1 specific T-cell responses were detected. Interpretation: Intramuscular administration of rAAV1-PG9DP in healthy men was safe and well-tolerated. Antibody expression was detected directly in muscle and indirectly in serum, and anti-drug antibodies were induced, indicating PG9 expression. Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralizing HIV antibodies. Trial Registration number: This trial is registered with ClinicalTrials.gov, number NCT01937455. Funding: International AIDS Vaccine Initiative, United States Agency for International Development (USAID), Bill & Melinda Gates Foundation, US National Institutes of Health Declaration of Interest: Jim Ackland reports receiving consulting fees from International AIDS Vaccine Initiative during the course of the study. Fraser Wright reports grants from National Institutes of Health during the conduct of the study. In addition, Dr. Wright has a patent US 9,408,904 licensed to Spark Therapeutics. Ethical Approval: The protocol was approved by the University of Surrey Ethics Committee, the NRES Bristol Research Ethics Committee and the UK Medicines and Healthcare products Regulatory Authority and conducted in compliance with Good Clinical Practices and the Declaration of Helsinki guidelines.

Background Digital technologies, especially if used in novel ways, provide a number of potential advantages to clinical research in trials related to human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) and may greatly facilitate operations as well as data collection and analysis. These technologies may even allow answering questions that are not answerable with older technologies. However, they come with a variety of potential concerns for both the participants and the trial sponsors. The exact challenges and means for alleviation depend on the technology and on the population in which it is deployed, and the rapidly changing landscape of digital technologies presents a challenge for creating future-proof guidelines for technology application. Objective The aim of this study was to identify and summarize some common themes that are frequently encountered by researchers in this context and highlight those that should be carefully considered before making a decision to include these technologies in their research. Methods In April 2016, the Global HIV Vaccine Enterprise surveyed the field for research groups with recent experience in novel applications of digital technologies in HIV clinical research and convened these groups for a 1-day meeting. Real-world uses of various technologies were presented and discussed by 46 attendees, most of whom were researchers involved in the design and conduct of clinical trials of biomedical HIV prevention and treatment approaches. After the meeting, a small group of organizers reviewed the presentations and feedback obtained during the meeting and categorized various lessons-learned to identify common themes. A group of 9 experts developed a draft summary of the findings that was circulated via email to all 46 attendees for review. Taking into account the feedback received, the group finalized the considerations that are presented here. Results Meeting presenters and attendees discussed the many successful applications of digital technologies to improve research outcomes, such as those for recruitment and enrollment, participant identification, informed consent, data collection, data quality, and protocol or treatment adherence. These discussions also revealed unintended consequence of technology usage, including risks to study participants and risks to study integrity. Conclusions Key lessons learned from these discussions included the need to thoroughly evaluate systems to be used, the idea that early success may not be sustained throughout the study, that some failures will occur, and considerations for study-provided devices. Additionally, taking these key lessons into account, the group generated recommendations on how to move forward with the use of technology in HIV vaccine and biomedical prevention trials.

Background: Health-care providers form the backbone of health information and service delivery in many African communities. This study investigated health-care providers' (HCPs) attitudes towards a novel method of HIV prevention for women—a microbicide-embedded intravaginal ring (IVR). Methods: Qualitative interviews were conducted, covering initial attitudes towards IVRs, potential use among female sex workers, herbal practices for sexually transmitted infection (STI) management and the ways in which populations can access the rings should they become available. Twenty HCPs were interviewed in Mukuru and Kibera, which are informal settlements in Nairobi, Kenya, with high HIV prevalence, unemployment and commercial sex work. Results: The majority of HCPs had positive attitudes towards IVRs as a method of HIV prevention in this environment. HCPs liked that IVRs are female controlled and can be used covertly. Overall, HCPs reported a willingness to participate in the distribution of IVRs, and favoured distribution through health facilities at no cost. Conclusion: Findings from this study demonstrate that HCPs are willing to serve as the primary source of IVR information in target communities. However, they require adequate knowledge regarding microbicides and IVRs before these products reach the market.

Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on-site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness.

Multiple intravaginal HIV prevention methods, including microbicide gels, barriers, and intravaginal rings, are in clinical development in Africa. Development of intravaginal HIV prevention products requires an understanding of sexual behavior, sexually transmitted infection (STI), and vaginitis prevalences, and sexual and vaginal practices in potential target populations. We assessed these factors in a cohort of Kenyan female sex workers (FSW). Women who reported exchanging sex for money/gifts at least three times in the past month and who were HIV uninfected were enrolled and followed for 6 months. STI prevalence and HIV incidence were analyzed by multivariate logistic regression analysis, controlling for demographic and behavioral factors. Thirty-seven percent (74/200) reported having had anal sex. Frequency of anal sex was higher with regular and casual partners than with primary partners. Women were less likely to use condoms for anal sex than for vaginal sex with regular or casual partners. Vaginal washing was universal (100%). HIV incidence was 5.6 per 100 person-years (95% CI 1.62, 11.67). HIV incidence was not associated with any demographic or risk behavior. The relatively high rate of anal sex and universal vaginal washing may complicate both safety and efficacy evaluation of intravaginal products and should be taken into account in trial design. This FSW population had significant HIV incidence and needs continued HIV prevention interventions.

Anti-HIV Antibodies One of the top priorities for an HIV vaccine is the ability to elicit a broadly neutralizing antibody response, which should provide the best protection against infection. In the 25 years since the discovery of HIV, very few broadly neutralizing antibodies have been identified, and those that do exist were discovered nearly two decades ago. Using a high-throughput culture system, Walker et al. (p. 285 ; published online 3 September) now identify two additional broadly neutralizing antibodies isolated from a clade A HIV-infected African donor. These antibodies exhibit great potency and, in contrast to other known broadly neutralizing antibodies, are able to neutralize a wide range of viruses from many different clades. The antibodies recognize a motif in the trimerized viral envelope protein that is found in conserved regions of the variable loops of the gp120 subunit. Identification of this motif provides an intriguing new target for vaccine development.

This study sought to determine if microdermabrasion can selectively remove stratum corneum to increase skin permeability. Although, microdermabrasion has been used for cosmetic treatment of skin for decades, no study has assessed the detailed effects of microdermabrasion conditions on the degree of skin tissue removal. Therefore, we histologically characterized the skin of rhesus macaques and human volunteers after microdermabrasion at different conditions. Using mobile tip microdermabrasion, an increase in the number of treatment passes led to greater tissue removal ranging from minimal effects to extensive damage to deeper layers of the skin. Of note, these data showed for the first time that at moderate microdermabrasion conditions selective yet full-thickness removal of stratum corneum could be achieved with little damage to deeper skin tissues. In the stationary mode of microdermabrasion, selective stratum corneum removal was not observed, but micro-blisters could be seen. Similar tissue removal trends were observed in human volunteers. As proof of concept for drug delivery applications, a model fluorescent drug (fluorescein) was delivered through microdermabraded skin and antibodies were generated against vaccinia virus after its topical application in monkeys. In conclusion, microdermabrasion can selectively remove full-thickness stratum corneum with little damage to deeper tissues and thereby increase skin permeability.

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of ≥100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-gamma ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers200 versusor =200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers200 versusor = 200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process. (c) 2007 Lippincott Williams & Wilkins.

Background These two trials under Europe-Africa collaborations aim at addressing two factors relevant for Africa i.e helminth infections and HIV-1 diversity. EV06 used a novel combination of DNA expressing clade C Env, Gag and Pol-nef co-administered with AIDSVAX®B/E Env protein to study the effect of S. mansoni on vaccine responses. GREAT is a recently awarded trial using a 2nd generation improved conserved tHIVConsvX T-cell vaccine candidate combined with bivalent mosaic design to increase breadth and protective epitopes. Methods EV06 enrolled 72 males and females aged 18–45, half infected with S. mansoni (SM+). In each arm 30 received vaccine and 6 placebo at week 0, 4 and 24. Responses were evaluated at week 0, 6, 26 and 36. Humoral responses were measured as binding IgG against a panel of HIV-1 envelope glycoproteins and as neutralizing antibodies (Nabs), using TZM/ bl cells and tier 1 pseudoviruses. Cellular responses were measured as HIV-specific CD4+ and CD8+ T-cell by IFN-γ ELIS-pot and multi-cytokine intracellular staining flow cytometry. GREAT will be a phase IIa trial and preparation for efficacy trials in Kenya, Uganda and Zambia testing ChAdOx1.tHIVconsv5 and ChAdOx1.tHIVconsv6 followed by MVA.tHIVconsv3 and MVA.tHIVconsv4 on week 2 (Arm 1) or week 8 (Arm 2). Progress Differences in binding IgG response rates were observed in vaccinated participants against the vaccine matched clade C V1V2 (gp70–96ZM651.02 V1V2) at week 6: 56% among SM+ versus 86% among SM – (p=0.039). At week 36, response magnitudes were statistically lower in the SM+ against gp120 and gp140 proteins (p=0.04 for both). SM+ also had lower Nabs and ELISpot responses at various time points. Still blinded data on the first 20 volunteers show 80% responders for CD4 T cell at w26 and 70% CD8 responders at w36. These trials will provide more data on challenges facing HIV vaccine development in Africa.

Yellow fever is a mosquitoborne hemorrhagic disease that is endemic in sub-Saharan Africa and tropical South America. The etiologic agent, the yellow fever virus (YFV) is a single-stranded RNA virus in the family Flaviviridae, which also includes the dengue and West Nile viruses. After a natural YFV infection, viral replication initially occurs in tissues at the site of infection, but it rapidly spreads to the lymph nodes, blood, and liver [1]. The live attenuated yellow fever vaccine (YF-17D) was developed in the 1930s through experimental attenuation of the Asibi strain of YFV by serial passaging in cell culture [2]. The vaccine is considered safe and extremely effective, and it has been administered to >500 million people worldwide [3, 4]. Protection is achieved in >98% of recipients, with a duration of at least 10 years and probably much longer, given that significant neutralizing antibody titers may persist for ≥35 years after a single vaccination [3, 4]. Although YF-17D is usually a well-tolerated vaccine, in rare cases (approximately 1 in 250,000 vaccinees) individuals develop severe viscerotropic adverse reactions within 2 to 5 days after vaccination; these reactions are sometimes fatal [5–8]. Yellow fever vaccine–associated viscerotropic disease is characterized by the failure of multiple organ systems [5–8]. Within 2–5 days after vaccination, patients develop high fever, malaise, and myalgia, followed by jaundice, oliguria, cardiovascular instability, hemorrhage, and renal and respiratory failure. The case fatality rate is over 50%, and large amounts of YFV antigen may be found in the liver, heart, and other organs, primarily in tissue-associated macrophages [5–9]. The syndrome was first described in 2001, but cases in 1975 and the 1990s were identified retrospectively. To date, a total of 36 cases have been reported worldwide. Genetic mutations in the YFV do not seem to be the cause of the adverse reactions, because in several instances YFV isolated from subjects has had the same consensus nucleotide sequence as the original vaccine strain virus [8]. Furthermore, the YFV isolates recovered from the subjects showed no reversion to virulence in animal models, suggesting that host factors may be involved in disease [8].

Few studies have examined the influence of pregnancy and hormonal contraception on HIV-related deaths in African women. Rwanda is a country with high fertility, high HIV prevalence, and frequent use of hormonal contraception in urban areas.Data from a prospective cohort study of 460 HIV-infected urban childbearing (18-35 years) women followed at 6-monthly intervals for 6 years in Kigali, Rwanda, were analyzed. The relationship of time-dependent measures of pregnancy and hormonal contraceptive use to death from HIV disease was assessed with multivariate models.Incident pregnancy was not associated with elevated risk of death among HIV-infected women. Oral and injectable hormonal contraceptive use had borderline protective effects associated with reduced mortality (HR 0.40, 95% CI 0.15-1.07 and HR 0.48, 95% CI 0.21-1.08 for mortality, respectively) in a multivariate model including time-dependent measures.The results point to the benefits of integrating family planning and HIV services. In a highly pronatalist society, such as Rwanda, which is experiencing high HIV prevalence, service integration affords an opportunity to provide HIV testing to women at risk of pregnancy and to promote family planning among HIV-positive women.

The southeastern United States has an increasing burden of HIV, particularly among blacks, women, and men who have sex with men. To evaluate HIV nucleic acid amplification testing (NAAT) and antibody-based algorithms in determination of HIV incidence, detection of acute HIV infections, and surveillance of drug-resistant virus transmission in the urban southeastern United States, we conducted a cross-sectional analysis of prospectively collected data from 2202 adults receiving HIV testing and counseling at 3 sites in Atlanta, GA from October 2002 through January 2004. After standard testing with an HIV enzyme immunoassay (EIA) and Western blot confirmation, HIV-positive specimens were tested with 2 standardized assays to detect recent infection. HIV antibody-negative specimens were pooled and screened for HIV using NAAT. Seventy (3.2%) of 2202 subjects were HIV infected. Only 66 were positive on the standard HIV antibody test; 4 were antibody-negative but acutely HIV infected. The overall annual HIV incidence was 1.1% (95% confidence interval [CI]: 0.4 to 1.8) based on the Vironostika-LS assay and 1.3% (95% CI: 0.6 to 2.1) based on the BED Incidence Enzyme Immunoassay (EIA). The prevalence of acute HIV infection was 1.8 per 1000 persons (95% CI: 0.7 to 4.6). The sensitivity of the current testing algorithm using an EIA and Western blot test for detectable infections was only 94.3% (95% CI: 86.2 to 97.8). All 3 of the acutely infected subjects genotyped had drug resistance mutations, and 1 had multiclass resistance. Adding NAAT-based screening to standard HIV antibody testing increased case identification by 6% and uncovered the first evidence of multidrug-resistant HIV transmission in Atlanta. Antibody tests alone are insufficient for public health practice in high-risk urban HIV testing settings.

Background Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses. Methods In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured. Results The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration. Conclusion Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses. Trial Registration ClinicalTrials.gov NCT01264445

Racial/ethnic minorities in the Southeastern USA are disproportionately affected by HIV, and would benefit from a preventive vaccine. We conducted a cross-sectional survey of 220 community college students in Atlanta to evaluate racial/ethnic differences in knowledge and willingness to participate in HIV vaccine trials. Willingness to participate did not differ by race/ethnicity, age, or gender, and was not associated with knowledge. African-Americans and Asians were more likely than Whites to: believe that an HIV vaccine exists, but is being withheld from the public; believe that AIDS was caused by a government conspiracy; feel that having other participants and investigators of their ethnic background in the trial was important. Misconceptions regarding HIV vaccines are common and differ by race/ethnicity. However, willingness to participate was not associated with knowledge or race/ethnicity. Efforts to increase participation should address the ethnic diversity of the trial personnel, and education to eliminate misconceptions about HIV vaccines and trials.

The potential medical transmission of HIV through unsafe medical injections was evaluated in 16 rural health institutions in Ethiopia. Most institutions reported re-using disposable needle/syringes, and 12% of observed injections were given with used, disposable syringes prepared for re-use. Analysis of used needle flushes showed no HIV RNA; however, the sensitivity of our method was limited. Despite the re-use of disposable needles, medical injection practices are not likely to contribute significantly to HIV transmission in this region.

During the first decade of the AIDS epidemic the outcome for nearly every person infected with HIV around the world was virtually the same: most of those who became infected with HIV eventually died as a result of AIDS. However this began to change in 1996 with the advent of protease inhibitors and HAART. In a very short time we saw dramatic decreases in the morbidity and mortality associated with HIV infection throughout the developed world and as a result the gap between outcomes for HIV-infected persons in the developed world and outcomes for those in the developing world began to widen. This unacceptable inequity between the countries that bear the greatest burden of disease and those that benefit the most from therapy is now beginning to change thanks largely to the efforts of nongovernmental organizations such as Medecines Sans Frontieres (MSF) and initiatives such as the President’s Emergency Plan For AIDS Relief and the “3 by 5” strategy of the World Health Organization (WHO). The WHO estimates that as a result of such programs the estimated number of people receiving antiretroviral therapy in the developing world increased from 400000 to 700000 during the second half of 2004. However this number still represents only ~12% of the nearly 6 million people who are in dire need of antiretroviral treatment. (excerpt)