Britta Wahren Project
World HIV Day December 1st 2016 - Britta Wahren Interviewed
MTC researcher Professor Britta Wahren has been interviewed by Swedish National Radio (SverigesRadio P4) to mark World Aids Day on 1st December.
The interview looks at how far research has progressed with the development of an HIV vaccine.
An effective HIV vaccine
Genetic vaccines have generated wide-spread interest for many applications, since DNA encoding a microbial gene results in in vivo expression of the desired gene, protein production and presentation as an endogenous foreign antigen. Due to these properties the polymorphic H LA system of humans can be targeted even with highly variable virus proteins, such as Human immunodeficiency virus (HIV), hepatitis C virus (HCV) or influenza.
HIV genes were constructed covering the highly variable sites of HIV envelopes and structural genes of Gag, subtypes A-E, the less variable parts of HIV regulatory genes and enzymes. Immunodominant non-neutralizing sequences were mutated, certain genes were changed to reduce toxicity and partial codon optimization was made to increase expression. Small size plasmids as well as divided doses of dominant versus subdominant genes together show potent and broad immunological cross-reactivity. A boost with recombinant vaccinia-based vector including subtypes A and E genes effectively activated innate, humoral functional, helper cell, and cytotoxic responses, with memory retained up to over 1 year preclinically and over 3 years in the clinic. This vaccine prime boost schedule has resulted in a very high immunogenicity in a clinical phase 1 prophylactic studies (last publ Joachim et al 2016). We performed phase 2 clinical studies in Tanzania, Mocambique, Sweden and a pediatric immunoprophylactic study in children in Italy (Palma et al 2011-2015).
The DNA technology was also used to produce a targeting antibody directed against sensitive sites of the HIV-infected cell and virions. In a collaboration with US-based Immunomedics, the construction of this new class of anti-HIV agents was enabled using proprietary Dock-and-Lock (DNL) technology. The new molecules have three distinguished features. First, each comprises four copies of T20 (enfuvirtide), an approved peptide that prevents the virus from infecting immune cells. Second, the multiple peptides are linked to a humanized antibody without compromising their activity. Third, the incorporation of the peptides to the antibody confers additional benefits, such as enhanced anti-viral potency and improved pharmacokinetics. As a result, both infected cells and activated enhanced virus replication have been destroyed in cell culture and in vivo in infected animals. The concurrent plan is to prove viral decrease in monkeys, and to take the antiviral antibody to a small human trial. This constitutes a new class of drugs that significantly destroys the virus HIV as well as the infected cells. It has the (Human Immunodeficiency Virus), and may potentially eradicate the virus completely (Chang et al 2012-2016).
An interview with Britta Wahren October 2015
After receiving the KI Silver medal 2015 for outstanding achievement in the field of medical research, Britta Wahren talks about her research past and present
Involved in recent theses and examination works
Athina Kilpeläinen, mentor
PhD in Barcelona 2016- xxx
Lena Hansen, co-tutor with Karl Ljungberg
Strategies to enhance the immune response to HIV envelope
Read the Master´s thesis, University of Bergen
Stefan Petkov, co-tutor
In vivo bioluminescence imaging in preclinical trials of genetic vaccines
Read the Lic thesis, KI
Sofia Stenler, involved in minicircle synthesis, PI P Blomberg
Read the PhD thesis
Strategies to enhance the potency of HIV-1 DNA vaccines
• Read the Thesis (Pdf file, 1 Mb)
Rebecca Axelsson Robertson
Development of MHC class I African alleles and ex vivo detection of M.tuberculosis-reactive CD8+ T-cells
• Read the Thesis (Pdf file, 2 Mb)
HIV-1 immune responses induced by natural infection or immunisation
• Read the Thesis (Pdf file, 2 Mb)
Vaccination against drug-resistant HIV
• Read the Thesis (Pdf file, 1 Mb)
Susanne Johansson: Immunotherapy in cancer and HIV.
• Read the Thesis, KI
Regulatory T cell abundance and activation status before and after priming with HIVIS-DNA and boosting with MVA-HIV/rgp140/GLA-AF may impact the magnitude of the vaccine-induced immune responses.
Immunobiology 2018 Dec;223(12):792-801
Codon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity.
Sci Rep 2018 May;8(1):8078
Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers.
AIDS Res. Hum. Retroviruses 2017 08;33(8):880-888
Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial.
PLoS ONE 2016 ;11(5):e0155702
Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission.
Lancet Infect Dis 2015 Sep;15(9):1108-1114
Short communication: HIV-1 Nef protein carries multiple epitopes suitable for induction of cellular immunity for an HIV vaccine in Africa.
AIDS Res. Hum. Retroviruses 2014 Nov;30(11):1065-71
Micro-minicircle Gene Therapy: Implications of Size on Fermentation, Complexation, Shearing Resistance, and Expression.
Mol Ther Nucleic Acids 2014 Jan;2():e140
Broad and potent cellular and humoral immune responses after a second late HIV-modified vaccinia virus ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccinees.
AIDS Res. Hum. Retroviruses 2014 Mar;30(3):299-311
A combination of intradermal jet-injection and electroporation overcomes in vivo dose restriction of DNA vaccines.
Genet Vaccines Ther 2012 Aug;10(1):5
The viral diversity and latency of HIV-1 is likely to require a vaccine strategy that induces broad cellular and humoral anti-HIV-1 immunity. Our strategy is based on multiple HIV-1 DNA immunogens together with adjuvants, proteins and/or viral vector boosts. The vaccines are currently being tested in clinical HIV-1 phase I/II trials in Sweden, a trial in children in Italy and several phase II trials in Tanzania and Mocambique.
We investigate the short and long-term immunity in previously vaccinated HIV infected patients. Cells of the innate defense contribute to induction of specific immunity and to long-term prognosis of infection. Both phenotypic and functional changes in the NK-cell population are analyzed together with specific immunity. Antiviral therapy suppresses HIV replication but may select drug-resistant HIV variants. Therefore we will immunize patients against the most common drug-resistant variants of the virus.
- Genetic vaccines against HIV-1
MD, Foreign Adjunct Professor at MTC/KI Margaret A. Liu
Work: +46 (0)8 457 2630
Work: alt. +19252992559, +19
Fax: +46 (0)8 337272
Margaret A. Liu, who graduated from Harvard Medical School, has been Visiting professor at KI and is now Foreign Adjunct professor at MTC/KI. She has served as Senior Director at Merck Research Laboratories, Vice President of Vaccines Research and Gene Therapy at Chiron Corporation, Vice-Chairman of Transgene, and Senior Advisor in Vaccinology at the Bill and Melinda Gates Foundation and she is advisory for several international vaccine programs. She was the senior investigator of the efficacy of genetic vaccines in ground breaking studies on influenza, tumor viruses and HIV.
Work: +46 (0)8 457 2691
Fax: +46 (0)8 337272
Gunnel has developed means for production and purification of DNA plasmids, and determined immunomodulatory effects of DNA as plasmids or as oligodeoxynucleotides. She is involved in clinical vaccine trials, for example the prophylactic vaccine project HIVIS where she is evaluating the bio-distribution of the vaccine plasmids in both preclinical and clinical settings. Issues regarding documentation for the Medical Products Agency (Läkemedelsverket) and reports on European union financed projects is handled through Gunnel.
Postdoc Kristian Hallermalm
Kristian received his Ph.D. from Karolinska Institutet in 2004. His previous work includes studies on how to improve immune recognition of tumors and the identification of new mechanisms of tumor immune escape. In his current projects Kristian is developing new molecular adjuvants for DNA vaccination. Another part of his work concerns clinical evaluation of DNA vaccination strategies in humans.
Professor at Linköping University
Immunologist and virologist developed a mouse model system for HIV replication and production. He is now a professor at the Department of Molecular and Clinical Medicine, Linköping University. He is still intensively involved in studies of mucosal immunity and establishing new small animal models for HIV.
MD, PhD Bo Hejdeman
Bo Hejdeman at the South Hospital, Karolinska Institutet is a close collaborator in HIV vaccine studies.
MD, PhD, Professor Eric Sandström
Eric Sandström at the South Hospital, Karolinska Institutet is a close collaborator in HIV vaccine studies.
MD, PhD, senior Professor Gunnel Biberfeld
Gunnel Biberfeld is a close collaborator in HIV vaccine studies.