International AIDS Vaccine Initiative Research Articles

Adaptation of an rVSV Ebola vaccine purification process for rapid development of a viral vaccine candidate for SARS-CoV-2.

During the COVID-19 pandemic, long development timelines typically associated with vaccines were challenged. The urgent need for a vaccine provided a strong driver to reevaluate existing vaccine development approaches. Innovative approaches to regulatory approval were realized, including the use of platform-based technology. In collaboration with the International AIDS Vaccine Initiative, Inc. (IAVI), Merck & Co., Inc., Rahway, NJ, USA rapidly advanced an investigational SARS-CoV-2 vaccine based on the recombinant vesicular stomatitis virus (rVSV) platform used for the Ebola vaccine ERVEBO (rVSV∆G-ZEBOV-GP). An rVSV∆G-SARS-CoV-2 vaccine candidate was generated using the SARS-CoV-2 spike protein to replace the VSV G protein. The purification process development for this vaccine candidate was detailed in this paper. Areas were highlighted where the ERVEBO platform process was successfully adopted and where additional measures were needed for the SARS-CoV-2 vaccine candidate. These included: (i) endonuclease addition directly into the bioreactor prior to harvest, (ii) inclusion of a core-shell chromatography step for improved purification, and (iii) incorporation of a terminal, sterile filtration step to eliminate the need for aseptic, closed processing. High infectious virus titers were achieved in Phase 3 clinical drug substance (>108 PFUmL-1 ), and process consistency was demonstrated across four large scale batches that were completed in 6 months from clone selection.

Recent outbreaks of Marburg virus in Africa: an urgent call for public concern

Recent outbreaks of Marburg virus in Africa: an urgent call for public concern

The human vaccines project: into the immunome

The Human Genome Project revolutionized biomedical research. Could mapping the immune system be the next frontier for human health? We caught up with the founder and CEO of the Human Vaccines Project, Wayne Koff, to find out how the initiative aims to decode the immune system and speed up vaccine development.Charlotte Barker, Editor, Vaccine Insights speaks to Wayne Koff, Human Vaccines Project & Harvard TH Chan School of Public HealthWayne Koff, PhD, is the founding president and CEO of the Human Vaccines Project and adjunct professor of epidemiology at the Harvard T.H. Chan School of Public Health. Prior to joining the Human Vaccines Project, Koff was chief scientific officer and senior vice president of research and development at the International AIDS Vaccine Initiative (IAVI) in New York City for 17 years. Earlier in his career, Koff held leadership roles including vice president of vaccine research and development at United Biomedical Inc. (UBI) and chief of the Vaccine Research and Development Branch, Division of AIDS, at the National Institute of Allergy and Infectious Diseases. An internationally recognized viral immunologist in the field of AIDS vaccine research and development, he has been twice honored by the US Department of Health and Human Services with the Special Act of Service Award for developing innovative strategies for accelerating global efforts in AIDS vaccine development.

Preclinical immunogenicity and efficacy of a candidate COVID-19 vaccine based on a vesicular stomatitis virus-SARS-CoV-2 chimera

SummaryBackgroundTo investigate a vaccine technology with potential to protect against coronavirus disease 2019 (COVID-19) and reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a single vaccine dose, we developed a SARS-CoV-2 candidate vaccine using the live vesicular stomatitis virus (VSV) chimeric virus approach previously used to develop a licensed Ebola virus vaccine.MethodsWe generated a replication-competent chimeric VSV-SARS-CoV-2 vaccine candidate by replacing the VSV glycoprotein (G) gene with coding sequence for the SARS-CoV-2 Spike glycoprotein (S). Immunogenicity of the lead vaccine candidate (VSV∆G-SARS-CoV-2) was evaluated in cotton rats and golden Syrian hamsters, and protection from SARS-CoV-2 infection also was assessed in hamsters.FindingsVSV∆G-SARS-CoV-2 delivered with a single intramuscular (IM) injection was immunogenic in cotton rats and hamsters and protected hamsters from weight loss following SARS-CoV-2 challenge. When mucosal vaccination was evaluated, cotton rats did not respond to the vaccine, whereas mucosal administration of VSV∆G-SARS-CoV-2 was found to be more immunogenic than IM injection in hamsters and induced immunity that significantly reduced SARS-CoV-2 challenge virus loads in both lung and nasal tissues.InterpretationVSV∆G-SARS-CoV-2 delivered by IM injection or mucosal administration was immunogenic in golden Syrian hamsters, and both vaccination methods effectively protected the lung from SARS-CoV-2 infection. Hamsters vaccinated by mucosal application of VSV∆G-SARS-CoV-2 also developed immunity that controlled SARS-CoV-2 replication in nasal tissue.FundingThe study was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and The International AIDS Vaccine Initiative, Inc. (IAVI), New York, USA. Parts of this research was supported by the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the US Department of Defense.

PrEP uptake and adherence in relation to HIV-1 incidence among Kenyan men who have sex with men.

BackgroundData on HIV-1 incidence following programmatic pre-exposure prophylaxis (PrEP) uptake by men who have sex with men (MSM) are limited in sub-Saharan Africa.MethodsSince June 2017, MSM participating in an ongoing cohort study in Kenya were offered daily PrEP, assessed for PrEP uptake and adherence, and evaluated for HIV-1 acquisition monthly. We determined tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots 6–12 months after PrEP initiation, and tenofovir (TFV) concentrations and genotypic drug resistance in plasma samples when HIV-1 infection occurred. We assessed HIV-1 incidence by reported PrEP use.FindingsOf 172 MSM, 170 (98·8%) were eligible for PrEP, 140 (82·4%) started it, and 64 (57·7%) reported PrEP use at end of study. Of nine MSM who acquired HIV-1 [incidence rate: 3·9 (95% confidence interval (CI), 2·0–7·4) per 100 person-years (PY)], five reported PrEP use at the time of HIV-1 acquisition [incidence rate: 3·6 (95% CI, 1·5–8·6) per 100 PY)] and four had stopped or had never started PrEP [incidence rate: 4·3 (95% CI, 1·6–11·3) per 100 PY]. Among 76 MSM who reported PrEP use, 11 (14·5%) had protective TFV-DP concentrations of ≥700 fmol/punch (≥4 tablets a week). Among the five MSM who acquired HIV-1 while reporting PrEP use, only one had detectable but low TFV concentrations in plasma and none had genotypic HIV-1 resistance.InterpretationHIV-1 incidence among MSM with access to programmatic PrEP was high and did not differ by reported PrEP use. Only one in seven MSM taking PrEP had protective tenofovir concentrations and four out of five MSM who acquired HIV-1 while reporting PrEP use had not taken it. Strengthened PrEP adherence support is required among MSM in Kenya.FundingThis work was supported by the International AIDS Vaccine Initiative (IAVI).

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective.

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective.

PO 8300 REGIONAL CENTER FOR REGULATORY EXCELLENCE IN CLINICAL TRIAL OVERSIGHT – TRAINING 2017

BackgroundThe competencies of the various national medicines regulatory agencies (NMRAs) in Africa vary which leads to generally porous regulatory systems for clinical trial oversight. Consequently, many trials have been conducted under unacceptable conditions compromising participants’ safety and data credibility and resulted in questionable outcomes that are used for making scientific judgement in addressing issues of public health in Africa.To improve the safety and quality of health technologies in Africa, the New Partnership for African Development (NEPAD) agency launched a programme to designate Regional Centres of Regulatory Excellence (RCOREs) with the specific objective of bridging existing gaps between African NMRAs through strengthening regulatory capacity of African Union member states. The Food and Drugs Authority (FDA), Ghana, was designated as RCORE for Clinical Trials oversight in May 2014.MethodsTo achieve the RCORE objectives, the FDA collaborated with the School of Public Health (SPH), University of Ghana to develop a training manual and piloted a training programme with funds from the International AIDS Vaccine Initiative (IAVI) through NEPAD.The programme, consisting of 4 compulsory modules, was organised from 6–30 November 2017 for 10 participants from Zambia, Sierra Leone, Liberia, Rwanda and Ghana. Interactive training methods in the form of theoretical and practical sessions were employed.ResultsThe pilot RCORE training was successful with expected training objectives achieved. Participants gained hands-on experience through activities like observing Good Clinical Practice inspection and a Technical Advisory Committee Meeting. Participants were given template tools to assist in developing regulatory guidelines and forms in their respective countries.A follow-up questionnaire was circulated to participants to assess the impact of the training on their work. Feedback „indicates that regulation of clinical trials has improved in their respective institutions.ConclusionThis pilot fellowship training was successful, „leading to the improvement of clinical trial regulation in the participating countries.

Induction of circulating T follicular helper cells and regulatory T cells correlating with HIV-1 gp120 variable loop antibodies by a subtype C prophylactic vaccine tested in a Phase I trial in India

A Phase I HIV-1 vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009 to test a subtype C prophylactic vaccine in a prime-boost regimen comprising of a DNA prime (ADVAX) and MVA (TBC-M4) boost. The trial demonstrated that the regimen was safe and well tolerated and resulted in enhancement of HIV-specific immune responses. Preliminary observations on vaccine-induced immune responses were limited to analysis of neutralizing antibodies and IFN-γ ELISPOT response. The present study involves a more detailed analysis of the nature of the vaccine-induced humoral immune response using specimens that were archived from the volunteers at the time of the trial. Interestingly, we found vaccine induced production of V1/V2 and V3 region-specific antibodies in a significant proportion of vaccinees. Variable region antibody levels correlated directly with the frequency of circulating T follicular helper cells (Tfh) and regulatory T cells (Treg). Our findings provide encouraging evidence to demonstrate the immunogenicity of the tested vaccine. Better insights into vaccine-induced immune responses can aid in informing future design of a successfulHIV-1 vaccine.

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)

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. 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. 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. 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). 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.

Adeno-Associated Virus Vectored Immunoprophylaxis to Prevent HIV: A Phase 1 Randomized Controlled Trial in Healthy Adults

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.

Detection and treatment of Fiebig stage I HIV-1 infection in young at-risk women in South Africa: a prospective cohort study

HIV incidence among young women in sub-Saharan Africa remains high and their inclusion in vaccine and cure efforts is crucial. We aimed to establish a cohort of young women detected during Fiebig stage I acute HIV infection in whom treatment was initiated immediately after diagnosis to advance research in this high-risk group. 945 women aged 18-23 years in KwaZulu-Natal, South Africa, who were HIV uninfected and sexually active consented to HIV-1 RNA testing twice a week and biological sampling and risk assessment every 3 months during participation in a 48-96 week life-skills and job-readiness programme. We analysed the effect of immediate combination antiretroviral therapy (ART) on viraemia and immune responses, sexual risk behaviour, and the effect of the socioeconomic intervention. 42 women were diagnosed with acute HIV infection between Dec 1, 2012, and June 30, 2016, (incidence 8·2 per 100 person-years, 95% CI 5·9-11·1), of whom 36 (86%) were diagnosed in Fiebig stage I infection with a median initial viral load of 2·97 log10 copies per mL (IQR 2·42-3·85). 23 of these 36 women started ART at a median of 1 day (1-1) after detection, which limited the median peak viral load to 4·22 log10 copies per mL (3·27-4·83) and the CD4 nadir to 685 cells per μL (561-802). ART also suppressed viral load (to <20 copies per mL) within a median of 16 days (12-26) and, in 20 (87%) of 23 women, prevented seroconversion, as shown with western blotting. 385 women completed the 48 week socioeconomic intervention, of whom 231 were followed up for 1 year. 202 (87%) of these 231 women were placed in jobs, returned to school, or started a business. Frequent HIV screening combined with a socioeconomic intervention facilitated sampling and risk assessment before and after infection. In addition to detection of acute infection and immediate treatment, we established a cohort optimised for prevention and cure research. Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, International AIDS Vaccine Initiative, Wellcome Trust, Howard Hughes Medical Institute.

Regulatory and Ethical Approval Timelines for HIV Vaccine Studies: An Analysis of International AIDS Vaccine Initiative (IAVI) Sponsored Studies in East and Southern Africa

Background: There has not been a systematic analysis of factors affecting ethics and regulatory timelines of HIV Vaccine trials and epidemiologic studies in Eastern and Southern Africa. We analyzed regulatory and ethics approval timelines and associated factors for HIV vaccine clinical trials and epidemiologic studies in Kenya, Uganda, Rwanda, South Africa and Zambia using data collected from seven Clinical Research Centers (CRCs) from 2001 to 2015. Methodology: Staff responsible for regulatory issues at CRCs provided archived data on ethical and regulatory review time-frames which were then validated with the sponsor central database. A semi structured questionnaires was administered to establish qualitative information on perceived factors affecting efficiency of approval processes and potential solutions. Quantitative data analysis was conducted using Excel. Qualitative data were analyzed using an open coding to analyze and elicit general themes. Findings: Data on submission for 23 clinical trials and 51 epidemiological study protocols were analyzed. Across all seven CRCs it took on average of 178 and 108 days to obtain full authorization to commence clinical trials and epidemiological studies, respectively. These timelines are shorter than the average found in other disease fields in Africa but seem longer than approval timelines in the USA and the EU that are estimated at 15-45 days and 43-75 days, respectively. We found that countries with sequential, rather than parallel, submission procedures had longer review timelines. Clinical trial approval timelines that were longer than 200 days were associated with amendment submissions prior to initial approval and with investigational products that required institutional biosafety committee reviews. Lengthier approval timelines were also associated with epidemiological studies with more invasive procedures. Conclusion: Strategies to further shorten timelines will need to focus on adoption of parallel approval processes; increase frequency of ethical review meetings and capacity strengthening of ethical review institutions.

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth.

A recent study of plasma neutralization breadth in HIV-1 infected individuals at nine International AIDS Vaccine Initiative (IAVI) sites reported that viral load, HLA-A*03 genotype, and subtype C infection were strongly associated with the development of neutralization breadth. Here, we refine the findings of that study by analyzing the impact of the transmitted/founder (T/F) envelope (Env), early Env diversification, and autologous neutralization on the development of plasma neutralization breadth in 21 participants identified during recent infection at two of those sites: Kigali, Rwanda (n = 9) and Lusaka, Zambia (n = 12). Single-genome analysis of full-length T/F Env sequences revealed that all 21 individuals were infected with a highly homogeneous population of viral variants, which were categorized as subtype C (n = 12), A1 (n = 7), or recombinant AC (n = 2). An extensive amino acid sequence-based analysis of variable loop lengths and glycosylation patterns in the T/F Envs revealed that a lower ratio of NXS to NXT-encoded glycan motifs correlated with neutralization breadth. Further analysis comparing amino acid sequence changes, insertions/deletions, and glycan motif alterations between the T/F Env and autologous early Env variants revealed that extensive diversification focused in the V2, V4, and V5 regions of gp120, accompanied by contemporaneous viral escape, significantly favored the development of breadth. These results suggest that more efficient glycosylation of subtype A and C T/F Envs through fewer NXS-encoded glycan sites is more likely to elicit antibodies that can transition from autologous to heterologous neutralizing activity following exposure to gp120 diversification. This initiates an Env-antibody co-evolution cycle that increases neutralization breadth, and is further augmented over time by additional viral and host factors. These findings suggest that understanding how variation in the efficiency of site-specific glycosylation influences neutralizing antibody elicitation and targeting could advance the design of immunogens aimed at inducing antibodies that can transition from autologous to heterologous neutralizing activity.

Defining success with HIV pre-exposure prophylaxis: a prevention-effective adherence paradigm.

Clinical trial data have shown that oral pre-exposure prophylaxis (PrEP) is efficacious when taken as prescribed; however, PrEP adherence is complex and must be understood within the context of variable risk for HIV infection and use of other HIV prevention methods. Different levels of adherence may be needed in different populations to achieve HIV prevention, and the optimal methods for achieving the necessary adherence for both individual and public health benefits are unknown. Guidance for PrEP use must consider these questions to determine the success of PrEP-based HIV prevention programs. In this article, we propose a new paradigm for understanding and measuring PrEP adherence, termed prevention-effective adherence, which incorporates dynamic HIV acquisition risk behaviors and the use of HIV alternative prevention strategies. We discuss the need for daily PrEP use only during periods of risk for HIV exposure, describe key issues for measuring and understanding relevant behaviors, review lessons from another health prevention field (i.e., family planning), and provide guidance for prevention-effective PrEP use. Moreover, we challenge emerging calls for sustained, near perfect PrEP adherence regardless of risk exposure and offer a more practical and public health-focused vision for this prevention intervention.

Strengthening neglected tropical disease research through enhancing research-site capacity: an evaluation of a novel web application to facilitate research collaborations.

1 The Global Health Network, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, 2 Drugs for Neglected Disease Initiative (DNDi), Geneva, Switzerland, 3 Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C., United States of America, 4 International Aids Vaccine Initiative (IAVI), New York, New York, United States of America, 5 Clinical Unit, PATH Malaria Vaccine Initiative, Washington, D.C., United States of America, 6 AERAS Global TB Vaccine Foundation, Washington, D.C., United States of America, 7 Global Alliance for TB Drug Development, Pretoria, South Africa

Strengthening capacity for AIDS vaccine research: analysis of the Pfizer Global Health Fellows Program and the International AIDS Vaccine Initiative

BackgroundIndustry partnerships can help leverage resources to advance HIV/AIDS vaccine research, service delivery, and policy advocacy goals. This often involves capacity building for international and local non-governmental organizations (NGOs). International volunteering is increasingly being used as a capacity building strategy, yet little is known about how corporate volunteers help to improve performance of NGOs in the fight against HIV/AIDS.MethodsThis case study helps to extend our understanding by analyzing how the Pfizer Global Health Fellows (GHF) program helped develop capacity of the International AIDS Vaccine Initiative (IAVI), looking specifically at Fellowship activities in South Africa, Kenya, and Uganda. From 2005–2009, 8 Pfizer GHF worked with IAVI and local research centers to strengthen capacity to conduct and monitor vaccine trials to meet international standards and expand trial activities. Data collection for the case study included review of Fellow job descriptions, online journals, evaluation reports, and interviews with Fellows and IAVI staff. Qualitative methods were used to analyze factors which influenced the process and outcomes of capacity strengthening.ResultsFellows filled critical short-term expert staffing needs at IAVI as well as providing technical assistance and staff development activities. Capacity building included assistance in establishing operating procedures for the start-up period of research centers; training staff in Good Clinical Practice (GCP); developing monitoring capacity (staff and systems) to assure that centers are audit-ready at all times; and strategic planning for data management systems. Factors key to the success of volunteering partnerships included similarities in mission between the corporate and NGO partners, expertise and experience of Fellows, and attitudes of partner organization staff.ConclusionBy developing standard operating procedures, ensuring that monitoring and regulatory compliance systems were in place, training African investigators and community members, and engaging in other systems strengthening activities, the GHF program helped IAVI to accelerate vaccine development activities in the field, and to develop the organization’s capacity to manage change in the future. Our study suggests that a program of sustained corporate volunteering over several years may increase organizational learning and trust, leading to stronger capacity to advance and achieve NGO goals.

Science writing workshops for AIDS vaccine researchers in Africa

The International AIDS Vaccine Initiative (IAVI) is a global scientific and advocacy organisation dedicated to ensuring an AIDS vaccine for use worldwide. In Africa, IAVI partners with seven research centres who conduct vaccine trials and studies. This research requires extensive medical and scientific writing support, for regulatory submissions and for the publication of data. IAVI and its African partners publish widely in international peer-reviewed publications; however, African authors are underrepresented as first authors. To address this disparity, IAVI created and honed a series of science writing workshops that so far has reached 85 investigators.

Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.

Recognition and penetration of the HIV-1 Env glycan shield by potent broadly neutralizing antibodies

Conclusion Structural characterization and biochemical analysis of these antibodies have uncovered novel specificities to new glycan-dependent epitopes and reveal further mechanisms for viral neutralization. These new epitopes provide additional insights for neutralization of HIV-1 and how antibodies can bind and penetrate the glycan shield, a novel framework for structure-assisted vaccine design. This study was supported by the International AIDS Vaccine Initiative (IAVI), Ragon Institute of MGH, MIT and Harvard, and NIH AI84817.

An assessment of Good Participatory Practice Guidelines at HIV prevention research clinical centers in Eastern and Southern Africa

Background Compliance with ethical, regulatory, and scientific guidelines does not always guarantee consideration of external stakeholders’ concerns in research. In 2007, UNAIDS and AVAC: Global Advocacy for HIV Prevention developed the Good Participatory Practice (GPP) Guidelines to ensure community and stakeholder engagement in biomedical HIV prevention research. In 2010-2011, the International AIDS Vaccine Initiative (IAVI) and AVAC conducted the first comprehensive evaluation of perceptions, practices and recommendations for improvement of participatory practice at eight IAVI-sponsored research centers (RCs) in Eastern and Southern Africa.