Britta Wahren Project

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 (1). 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 with a potent adjuvant for DNA show potent and broad immunological cross-reactivity. A boost with recombinant vaccinia-based vector including subtypes A and E genes effectively activated innate, humoral, helper cell, and cytotoxic responses, with memory retained up to over 3 years. This vaccine prime boost schedule has resulted in a very high immunogenicity in a clinical phase 1 prophylactic studies (2). We performed phase 2 clinical studies in Tanzania, Mocambique, Sweden and a pediatric immunoprophylactic study in children in Italy.

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, Hoffmann-LaRoche), 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.

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

Research Rendezvous: an interview with Britta Wahren

    Other Britta Wahren Projects

    •    Andreas Bråve Project
    •    Jonas Klingström Project


Theses and Examination Work

David Hallengärd
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)

Lindvi Gudmundsdotter
HIV-1 immune responses induced by natural infection or immunisation
    •    Read the Thesis (Pdf file, 2 Mb)

Andreas Boberg
Vaccination against drug-resistant HIV
    •    Read the Thesis (Pdf file, 1 Mb)

Sarah Petersson
HIV-1 specific humoral immune responses in healthy volunteers after HIV DNA prime - HIV MVA boost immunization
Masters Biology
    •    Read the article (Pdf file, 1 Mb)

Micaela Ljunggren
Antibodies - Nature, Multispecificity and the Role in Host Defence Against HIV-Infection
     •   Read the article (Pdf file, 856 Kb)



Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission.
Klein N, Palma P, Luzuriaga K, Pahwa S, Nastouli E, Gibb D, et al
Lancet Infect Dis 2015 Sep;15(9):1108-14

Priming with a simplified intradermal HIV-1 DNA vaccine regimen followed by boosting with recombinant HIV-1 MVA vaccine is safe and immunogenic: a phase IIa randomized clinical trial.
Munseri P, Kroidl A, Nilsson C, Joachim A, Geldmacher C, Mann P, et al
PLoS ONE 2015 ;10(4):e0119629

Potent functional antibody responses elicited by HIV-I DNA priming and boosting with heterologous HIV-1 recombinant MVA in healthy Tanzanian adults.
Joachim A, Nilsson C, Aboud S, Bakari M, Lyamuya E, Robb M, et al
PLoS ONE 2015 ;10(4):e0118486

Short communication: HIV-1 Nef protein carries multiple epitopes suitable for induction of cellular immunity for an HIV vaccine in Africa.
Kilpeläinen A, Axelsson Robertson R, Leitner T, Sandström E, Maeurer M, Wahren B
AIDS Res. Hum. Retroviruses 2014 Nov;30(11):1065-71

Micro-minicircle Gene Therapy: Implications of Size on Fermentation, Complexation, Shearing Resistance, and Expression.
Stenler S, Wiklander O, Badal-Tejedor M, Turunen J, Nordin J, Hallengärd D, et al
Mol Ther Nucleic Acids 2014 ;2():e140

Therapeutic DNA vaccination of vertically HIV-infected children: report of the first pediatric randomised trial (PEDVAC).
Palma P, Romiti M, Montesano C, Santilli V, Mora N, Aquilani A, et al
PLoS ONE 2013 ;8(11):e79957

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.
Nilsson C, Godoy-Ramirez K, Hejdeman B, Bråve A, Gudmundsdotter L, Hallengärd D, et al
AIDS Res. Hum. Retroviruses 2014 Mar;30(3):299-311

Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness.
Nowroozalizadeh S, Gudmundsdotter L, Hejdeman B, Andersson L, Esbjörnsson J, Medstrand P, et al
Hum Vaccin Immunother 2013 Oct;9(10):2103-10

Oxidative stress induced by HIV-1 reverse transcriptase modulates the enzyme's performance in gene immunization.
Isaguliants M, Smirnova O, Ivanov A, Kilpelainen A, Kuzmenko Y, Petkov S, et al
Hum Vaccin Immunother 2013 Oct;9(10):2111-9

A truncated plasmid-encoded HIV-1 reverse transcriptase displays strong immunogenicity.
Hallengärd D, Wahren B, Bråve A
Viral Immunol. 2013 Apr;26(2):163-6

Immunization with multiple vaccine modalities induce strong HIV-specific cellular and humoral immune responses.
Hallengärd D, Applequist S, Nyström S, Maltais A, Marovich M, Moss B, et al
Viral Immunol. 2012 Oct;25(5):423-32

A combination of intradermal jet-injection and electroporation overcomes in vivo dose restriction of DNA vaccines.
Hallengärd D, Bråve A, Isaguliants M, Blomberg P, Enger J, Stout R, et al
Genet Vaccines Ther 2012 ;10(1):5

A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.
Chang C, Hinkula J, Loo M, Falkeborn T, Li R, Cardillo T, et al
PLoS ONE 2012 ;7(7):e41235

Safety and efficacy of HIV hyperimmune globulin for prevention of mother-to-child HIV transmission in HIV-1-infected pregnant women and their infants in Kampala, Uganda (HIVIGLOB/NVP STUDY).
Onyango-Makumbi C, Omer S, Mubiru M, Moulton L, Nakabiito C, Musoke P, et al
J. Acquir. Immune Defic. Syndr. 2011 Dec;58(4):399-407

NK cell function and antibodies mediating ADCC in HIV-1-infected viremic and controller patients.
Johansson S, Rollman E, Chung A, Center R, Hejdeman B, Stratov I, et al
Viral Immunol. 2011 Oct;24(5):359-68

Comparison of plasmid vaccine immunization schedules using intradermal in vivo electroporation.
Hallengärd D, Haller B, Maltais A, Gelius E, Nihlmark K, Wahren B, et al
Clin. Vaccine Immunol. 2011 Sep;18(9):1577-81

Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania.
Bakari M, Aboud S, Nilsson C, Francis J, Buma D, Moshiro C, et al
Vaccine 2011 Oct;29(46):8417-28

Safety and efficacy of HIV hyperimmune globulin for prevention of mother-to-child HIV transmission in HIV-1-infected pregnant women and their infants in Kampala, Uganda (HIVIGLOB/NVP STUDY).
Onyango-Makumbi C, Omer S, Mubiru M, Moulton L, Nakabiito C, Musoke P, et al
J. Acquir. Immune Defic. Syndr. 2011 Dec;58(4):399-407

Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial.
Gudmundsdotter L, Wahren B, Haller B, Boberg A, Edbäck U, Bernasconi D, et al
Vaccine 2011 Jul;29(33):5558-66

A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients.
Staff C, Mozaffari F, Haller B, Wahren B, Liljefors M
Vaccine 2011 Sep;29(39):6817-22

Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010.
Brinckmann S, da Costa K, van Gils M, Hallengärd D, Klein K, Madeira L, et al
J Transl Med 2011 ;9():40

The PEDVAC trial: preliminary data from the first therapeutic DNA vaccination in HIV-infected children.
Palma P, Romiti M, Li Pira G, Montesano C, Mora N, Aquilani A, et al
Vaccine 2011 Sep;29(39):6810-6

Increased expression and immunogenicity of HIV-1 protease following inactivation of the enzymatic activity.
Hallengärd D, Haller B, Petersson S, Boberg A, Maltais A, Isaguliants M, et al
Vaccine 2011 Jan;29(4):839-48

Biodistribution, persistence and lack of integration of a multigene HIV vaccine delivered by needle-free intradermal injection and electroporation.
Bråve A, Gudmundsdotter L, Sandström E, Haller B, Hallengärd D, Maltais A, et al
Vaccine 2010 Nov;28(51):8203-9

Strong HIV-specific CD4+ and CD8+ T-lymphocyte proliferative responses in healthy individuals immunized with an HIV-1 DNA vaccine and boosted with recombinant modified vaccinia virus ankara expressing HIV-1 genes.
Aboud S, Nilsson C, Karlén K, Marovich M, Wahren B, Sandström E, et al
Clin. Vaccine Immunol. 2010 Jul;17(7):1124-31

Potent cross-reactive immune response against the wild-type and drug-resistant forms of HIV reverse transcriptase after the chimeric gene immunization.
Starodubova E, Boberg A, Ivanov A, Latyshev O, Petrakova N, Kuzmenko Y, et al
Vaccine 2010 Feb;28(8):1975-86

NK cell activation by KIR-binding antibody 1-7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients.
Johansson S, Hejdeman B, Hinkula J, Johansson M, Romagné F, Wahren B, et al
Clin. Immunol. 2010 Feb;134(2):158-68

Induction of HIV-1-specific cellular and humoral immune responses following immunization with HIV-DNA adjuvanted with activated apoptotic lymphocytes.
Brave A, Johansson U, Hallengärd D, Heidari S, Gullberg H, Wahren B, et al
Vaccine 2010 Feb;28(9):2080-7

Neutralizing activity and cellular immune responses induced in mice after immunization with apoptotic HIV-1/murine leukemia virus infected cells.
Hinkula J, Walther-Jallow L, Laurén A, Mäkitalo B, Oberg M, Wahren B, et al
Vaccine 2009 Oct;27(46):6424-31

Skin electroporation: effects on transgene expression, DNA persistence and local tissue environment.
Roos A, Eriksson F, Timmons J, Gerhardt J, Nyman U, Gudmundsdotter L, et al
PLoS ONE 2009 ;4(9):e7226

Recombinant Modified Vaccinia Ankara (MVA) effectively boosts DNA-primed HIV-specific immune responses in humans despite pre-existing vaccinia immunity.
Gudmundsdotter L, Nilsson C, Brave A, Hejdeman B, Earl P, Moss B, et al
Vaccine 2009 Jul;27(33):4468-74

Late administration of plasmid DNA by intradermal electroporation efficiently boosts DNA-primed T and B cell responses to carcinoembryonic antigen.
Bråve A, Hallengärd D, Gudmundsdotter L, Stout R, Walters R, Wahren B, et al
Vaccine 2009 Jun;27(28):3692-6

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian-human immunodeficiency virus strain 89.6p-infected macaques.
Koopman G, Mortier D, Hofman S, Koutsoukos M, Bogers W, Wahren B, et al
J. Gen. Virol. 2009 Apr;90(Pt 4):915-26

Broad immunogenicity of a multigene, multiclade HIV-1 DNA vaccine boosted with heterologous HIV-1 recombinant modified vaccinia virus Ankara.
Sandström E, Nilsson C, Hejdeman B, Bråve A, Bratt G, Robb M, et al
J. Infect. Dis. 2008 Nov;198(10):1482-90

Vaccine delivery methods using viral vectors.
Bråve A, Ljungberg K, Wahren B, Liu M
Mol. Pharm. ;4(1):18-32

The rationale behind a vaccine based on multiple HIV antigens.
Rollman E, Bråve A, Boberg A, Gudmundsdotter L, Engström G, Isaguliants M, et al
Microbes Infect. 2005 Nov;7(14):1414-23

Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment.
Calarota S, Leandersson A, Bratt G, Hinkula J, Klinman D, Weinhold K, et al
J. Immunol. 1999 Aug;163(4):2330-8

Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients.
Calarota S, Bratt G, Nordlund S, Hinkula J, Leandersson A, Sandström E, et al
Lancet 1998 May;351(9112):1320-5


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Group Members

Professor, senior

Britta Wahren

Telefon: 08-524 859 98
Enhet: Francesca Chiodi grupp


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.

Principle projects:

  • Genetic vaccines against HIV-1
  • Long-term immunity in HIV-1 patients subjected to immunotherapy intervention
  • NK cells in HIV infection
  • Breadth of tolerance to tumor antigens


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.

Gunnel Engström
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.

PhD Andreas Bråve

Working with the development and evaluation of the genetic HIV vaccine that currently is in two clinical trials. Research includes studying effects of combining multiple immunogens and prime boost approaches using naked DNA in combination with viral vectors.

PhD student Susanne Johansson

Susanne presented her licentiate thesis on "Immunotherapy in cancer and HIV" in the spring 2006. She has investigated the immunogenicity induced by a DNA-vaccine encoding the tumor antigen carcinoembryonic antigen (CEA) in mice. She has also studied the effects of a drug-conjugated anti-HIV antibody in our HIV challenge model in mice. Now she is mainly focusing on the role of NK-cells during HIV infection, both in our HIV challenge model and in HIV infected patients.

PhD Andreas Boberg 

Andreas PhD-project concerns vaccine development targeting drug-resistant HIV. The project is primarily focused to reverse transcriptase and protease since antiretroviral drug-resistance associated mutations primarily take place within these proteins. Our hypothesis is that it may be possible to immunize patients against the most common drug-resistant variants of the virus before infection or therapeutically at the start of antiretroviral drug treatment. This may circumvent or suppress the development of resistant HIV variants.

PhD Erik Rollman
working currently as post-doc at the Univeristy of Melborne, Australia

The gene adjuvant effects of several compound was studied, exemplified by GM-CSF, ODNs and new compounds. He has established a new tecnique to obtain HIV subtypes that can be used in a murine model challenge system. He also investigates the molecular interactions that distinguish HIV replication in humans and in chimpanzees.

Professor at Linköping University
Jorma Hinkula

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 Göran Bratt
Göran Bratt 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.


  • Bartek Zuber
  • Anne Kjerrström
  • Karl Ljungberg
  • Soo Aleman
  • Anna-Lena Hammarin
  • Sandra Calarota
  • Ann-Charlotte Leandersson
  • Peter Lundholm
  • Reikei Matsuda, Yusuke Asakura and Kenji Okuda

Bartek Zuber
Bartek is involved in induction of immunity and break of tolerance by genetic immunization with viral receptor genes. He has also established a macaque model system for studies of drug sensitive and resistance HIV RT genes.

Anne Kjerrström Zuber
Anne studies the interactive influence of regulatory genes of the HIV genome for induction of immunity and interference of these immunities. Imiquimod has been found to have unexpected adjuvant effects to DNA immunization.

Soo Aleman
She presented her thesis "Studies on the efficacy of potent anti-HIV therapy on virological and immunological factors" in 2001 with prof. Anders Sönnerborg at the Karolinska Institutet. She investigated the mutations of the HIV nef gene during immunological pressure.

Aleman S, Leitner T, Liu MA, Wahren B.
Minor nef gene alterations after human HIV-DNA immunisation.
AIDS. 2004 Mar 26;18(5):817-9.

Anna-Lena Hammarin
Presented her lic exam on "Human polyoma viruses and central nervous system disease" in 1999 at the Karolinska Institutet. She is involved in establishing methodology for poxviruses, rabies and for detection of abnormal prion proteins in humans.

Cosma A, Buhler S, Nagaraj R, Staib C, Hammarin AL, Wahren B, Goebel FD, Erfle V, Sutter G.
Neutralization assay using a modified vaccinia virus Ankara vector expressing the green fluorescent protein is a high-throughput method to monitor the humoral immune response against vaccinia virus.
Clin Diagn Lab Immunol. 2004 Mar;11(2):406-10.

Sandra Calarota
Presented her thesis "The central role of the CD4 T-helper cell in HIV infection" at the Karolinska Institutet in 2001, the opponent was Col. Deborah Birx, Walter Reed Institute of Research, MD. She is working at the European Commission as a laboratory supervisor in Milan, for clinical chemistry and biochemistry.

Calarota, S., Bratt, G., Nordlund, S., Hinkula, J., Leandersson, A-C., Sandström, E. & Wahren, B
Cellular cytotoxicity induced by DNA vaccination of HIV-1 infected patients.
Lancet 351:1320-1325, 1998

Ann-Charlotte Leandersson
Presented her thesis "The central role of the CD4 T-helper cell in HIV infection" at the Karolinska Institutet in 2001, the opponent was Col. Deborah Birx, Walter Reed Institute of Research, MD. She is working at the European Commission as a laboratory supervisor in Milan, for clinical chemistry and biochemistry.

Leandersson, A-C., Gilljam, G., Fredriksson, M., Hinkula, J., Alaeus, A., Lidman, K., Albert, J., Bratt, G., Sandström, E. & Wahren, B.
Cross-reactive T-helper responses in patients infected with different subtypes of human immunodeficiency virus type 1.
J. Virol.,74:4888-4890, 2000

Peter Lundholm
Peter presented his thesis "Immune and autoimmune responses to HIV-1 in mucosa and other tissues" at Karolinska Institutet in 1999. The opponent was Prof Roland Jonsson, Univ. of Bergen, Norway. He is now established as a researcher Karolinska University Hospital, Huddinge. He developed a new means of delivering HIV genes mucosally in experimental animals and humans

Lundholm, P., Leandersson, A.C., Christensson, B., Bratt, G., Sandström, E. & Wahren, B
DNA mucosal HIV vaccine in humans.
Virus Res. 82:1-2, 141-145, 2002

Reikei Matsuda, Yusuke Asakura and Kenji Okuda
Researchers from Yokohama University, with whom we have a long standing collaboration in constuction of plasmids for HIV immunization and improvement of experimental techniques.

Matsuda R, Bostrom AC, Fredriksson M, Fredriksson EL, Bratt G, Hejdeman B, Sandström E, Okuda K, Wahren B.
Human immunodeficiency virus-type 1 specific cellular immunity in chronic infected patients on prolonged highly active antiretroviral treatment and on structured treatment interruption.
Microbiol Immunol. 2006;50(8):629-35.