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Scientific Publications

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Price MA, Kilembe W, Ruzagira E, Karita E, Inambao M, Sanders EJ, Anzala O, Allen S, Edward VA, Kaleebu P, Fast PE, Rida W, Kamali A, Hunter E, Tang J, Lakhi S, Mutua G, Bekker LG, Abu-Baker G, Tichacek A, Chetty P, Latka MH, Maenetje P, Makkan H, Hare J, Kibengo F, Priddy F, Landais E, Chinyenze K, Gilmour J

Cohort profile: IAVI's HIV epidemiology and early infection cohort studies in Africa to support vaccine discovery. Int J Epidemiol 2020; doi: dyaa100

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Bahemuka UM, Abaasa A, Seeley J, Byaruhanga M, Kamali A, Mayaud P, Kuteesa M

Feasibility of establishing an HIV vaccine preparedness cohort in a population of the Uganda Police Force: Lessons learnt from a prospective study. PLoS ONE 2020;15(4):e0231640 doi: 10.1371/journal.pone.0231640

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Members of uniformed armed forces are considered to be at high risk for HIV infection and have been proposed as suitable candidates for participation in HIV intervention studies. We report on the feasibility of recruitment and follow up of individuals from the community of the Uganda Police Force (UPF) for an HIV vaccine preparedness study.

Topics: Capacity Building and Research Preparedness

Tait DR, Meeren OV, Hatherill M

A Trial of M72/AS01E Vaccine to Prevent Tuberculosis. Reply. N. Engl. J. Med. 2020;382(16):1577 doi: 10.1056/NEJMc2001364

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Topics: Tuberculosis

Abaasa A, Nash S, Mayanja Y, Price MA, Fast PE, Kaleebu P, Todd J

Comparison of HIV Risk Behaviors Between Clinical Trials and Observational Cohorts in Uganda. AIDS Behav 2020; doi: 10.1007/s10461-020-02838-w

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Many key populations have high-risk behaviors for HIV infection making them suitable for HIV vaccine efficacy trials. However, these behaviors may change when participants enroll into a trial. We used HIV simulated vaccine efficacy trials (SiVETs) nested within observational cohorts of fisherfolks and female sex workers in Uganda to evaluate this difference. We screened observational cohort participants for enrolment into SiVETs, until 572 were enrolled. Those not enrolled (n = 953) continued participation in the observational cohorts. We determined risk behaviors at baseline and at 1 year, assigned a numeric score to each behavior and defined composite score as the sum of reported behaviors. We compared changes in scores over 12 months. Both observational cohorts and SiVETs saw a significant decrease in score but greatest in the SiVETs. Investigators recruiting for trials from these populations should consider the likely effect of reduction in risk behaviors on incident HIV infection and trial statistical power.

Topics: Capacity Building and Research Preparedness, First or Last Southern Author

Debebe BJ, Boelen L, Lee JC, Thio CL, Astemborski J, Kirk G, Khakoo SI, Donfield SM, Goedert JJ, Asquith B

Identifying the immune interactions underlying HLA class I disease associations. Elife 2020;9 doi: 10.7554/eLife.54558

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms in the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8 T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8 T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease.

Topics: HLA

Ols S, Yang L, Thompson EA, Pushparaj P, Tran K, Liang F, Lin A, Eriksson B, Karlsson Hedestam GB, Wyatt RT, Loré K

Route of Vaccine Administration Alters Antigen Trafficking but Not Innate or Adaptive Immunity. Cell Rep 2020;30(12):3964-3971.e7 doi: S2211-1247(20)30292-8

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Although intramuscular (i.m.) administration is the most commonly used route for licensed vaccines, subcutaneous (s.c.) delivery is being explored for several new vaccines under development. Here, we use rhesus macaques, physiologically relevant to humans, to identify the anatomical compartments and early immune processes engaged in the response to immunization via the two routes. Administration of fluorescently labeled HIV-1 envelope glycoprotein trimers displayed on liposomes enables visualization of targeted cells and tissues. Both s.c. and i.m. routes induce efficient immune cell infiltration, activation, and antigen uptake, functions that are tightly restricted to the skin and muscle, respectively. Antigen is also transported to different lymph nodes depending on route. However, these early differences do not translate into significant differences in the magnitude or quality of antigen-specific cellular and humoral responses over time. Thus, although some distinct immunological differences are noted, the choice of route may instead be motivated by clinical practicality.

Topics: HIV Vaccine Immunology

Nogal B, Bianchi M, Cottrell CA, Kirchdoerfer RN, Sewall LM, Turner HL, Zhao F, Sok D, Burton DR, Hangartner L, Ward AB

Mapping Polyclonal Antibody Responses in Non-human Primates Vaccinated with HIV Env Trimer Subunit Vaccines. Cell Rep 2020;30(11):3755-3765.e7 doi: S2211-1247(20)30229-1

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Rational immunogen design aims to focus antibody responses to vulnerable sites on primary antigens. Given the size of these antigens, there is, however, potential for eliciting unwanted, off-target responses. Here, we use our electron microscopy polyclonal epitope mapping approach to describe the antibody specificities elicited by immunization of non-human primates with soluble HIV envelope trimers and subsequent repeated viral challenge. An increased diversity of epitopes recognized and the approach angle by which these antibodies bind constitute a hallmark of the humoral response in most protected animals. We also show that fusion peptide-specific antibodies are likely responsible for some neutralization breadth. Moreover, cryoelectron microscopy (cryo-EM) analysis of a fully protected animal reveals a high degree of clonality within a subset of putatively neutralizing antibodies, enabling a detailed molecular description of the antibody paratope. Our results provide important insights into the immune response against a vaccine candidate that entered into clinical trials in 2019.

Topics: HIV Vaccine Immunology

Wahome E, Graham S, Thiong'o A, Chirro O, Mohamed K, Gichuru E, Mwambi J, Price M, Sanders EJ

Assessment of PrEP eligibility and uptake among at-risk MSM participating in a HIV-1 vaccine feasibility cohort in coastal Kenya. Wellcome Open Res 2019;4:138 doi: 10.12688/wellcomeopenres.15427.1

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Topics: Capacity Building and Research Preparedness

Munusamy Ponnan S, Hayes P, Fernandez N, Thiruvengadam K, Pattabiram S, Nesakumar M, Srinivasan A, Kathirvel S, Shankar J, Goyal R, Singla N, Mukherjee J, Chatrath S, Gilmour J, Subramanyam S, Prasad Tripathy S, Swaminathan S, Hanna LE

Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India. PLoS ONE 2020;15(2):e0229461 doi: 10.1371/journal.pone.0229461

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.

Topics: HIV Vaccine Immunology

Keywords: IAVI P001

Moyer TJ, Kato Y, Abraham W, Chang JYH, Kulp DW, Watson N, Turner HL, Menis S, Abbott RK, Bhiman JN, Melo MB, Simon HA, Herrera-De la Mata S, Liang S, Seumois G, Agarwal Y, Li N, Burton DR, Ward AB, Schief WR, Crotty S, Irvine DJ

Engineered immunogen binding to alum adjuvant enhances humoral immunity. Nat. Med. 2020; doi: 10.1038/s41591-020-0753-3

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.

Topics: HIV Immunogen Design

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