Research Interest

My group is carrying out cutting-edge research into HIV-1 vaccine development. In collaboration with other experts in the field, we explore novel approaches and emerging technologies to induce protective T-cell and neutralizing antibody responses. I oversee the conception, construction and stepwise improvements of new vaccine candidates in an iterative process from mouse to non-human primate models, followed by clinical studies in humans.

Designing an effective vaccine against HIV-1 is far from straightforward. The HIV-1 virus is highly mutable and thus highly variable, and it evolves to evade the adaptive arms of the immune system. Furthermore, during HIV-1 infection,immune responses are dominated by those targeting the most variable parts of proteins. These variable regions serve as decoys, which attract most of the attention of the immune responses, but easily change under their selective pressure. Mutated, unrecognized viruses then rapidly overgrow the targeted strains and replace them.

Scientists have employed a range of innovative solutions to combat these challenges. After being initially ignored, the problem of variability was tackled by creating immunogen cocktails from different HIV-1 isolates or amino acid average sequences. Efforts to make use of the growing HIV-1 sequence database and advent of increasing computing power has led Dr Bette Korber’s team at the Los Alamos National Laboratory, USA, to develop mosaic proteins. As artificial proteins assembled from all HIV-1 sequence variants in the database, these immunogens are computed over every HIV-1 protein to maximize the perfect match by vaccines of all the potential killer T-cell epitopes present in all circulating HIV-1 isolates.

We are studying the potential impact of vaccine-induced T-cells targeting the most functionally conserved regions of the HIV-1 proteome. This approach should generate effectors that pinpoint and kill the virus-infected cells soon enough after transmission to slow HIV-1 replication and prevent damage to the immune system. In general, focusing both T-cells and antibodies on functionally conserved regions is very attractive and possibly the most effective method for tackling the variability of pathogens.

Successful vaccine development requires systematic and iterative clinical trials using humans. We have pioneered clinical tests of HIV-1 vaccines that focus T-cell responses on the most conserved regions of the HIV-1 proteome. The first generation of the conserved T-cell immunogen, delivered by a combination of plasmid DNA, simian (chimpanzee) adenovirus ChAdV and modified vaccinia Ankara (MVA) in trial HIV-CORE 002, demonstrated safety and highly promising immunogenicity in terms of magnitude, persistence, breadth and functionality of the vaccine-elicited T-cell responses.

These promising initial observations are being incorporated into a broader programme that consists of six prophylactic and therapeutic trials of human adults in Europe and Africa, with the results set to emerge over the next one to two years. Recently, we collaborated with Korber to design second generation conserved region vaccines. Based on the mosaic proteins designed to enhance the T-cell epitope match with global HIV variants, these vaccines are currently being prepared for clinical tests. We aim to assess the T-cell induction by the second generation vaccines in a small bridging trial in Oxford, recruiting healthy, HIV-1-uninfectd humans. The data from the on-going programme and the bridging study will help define the future developmental path for the conserved region strategy.

According to the UNAIDS 2013 global report, over 700 children are newly infected with HIV-1 every day, with the majority acquiring the virus from their mothers. With only 57 per cent access to appropriate antiretroviral in 2012,there is an urgent need for both effective HIV-1 vaccines that decrease infection rates in mothers, and paediatric vaccines that protect infants against breast milk HIV-1 transmission. In 2007, we worked to develop a dual vaccine to protect newborns against both TB and HIV-1 infections. We proposed that the insertion of an HIV-1-derived immunogen into the scheduled BCG vaccine for TB, delivered soon after birth, could provoke HIV-1-specific responses, and thus potentially decrease mother-to-child HIV-1 transmission through breastfeeding. In 2010, I led randomized clinical trials that involved administering a candidate HIV-1 vaccine to 20-week-old infants born to HIV-1-negative mothers in The Gambia and HIV-1-positive mothers in Kenya. Promisingly, and similarly to the other published infant trials, the study demonstrated that it is feasible to test candidate HIV-1 vaccines in high-risk African infants. Furthermore, the results supported the use of MVA as a boosting vector within heterologous prime-boost vaccine strategies in the under-1- year age group.

Our key collaborators are Dr LucyDorrell, Professor Sir Andrew McMichael and DrBenedikt Kessler, University of Oxford; Professor Walter Jaoko, University of Nairobi, Kenya; Dr Bette Korber, Los Alamos National Laboratory, USA; The International AIDS Vaccine Initiative; Dr Katie Flanagan, formerly MRC Laboratories, The Gambia; Professor Grace John-Stewart, University of Washington, USA; Professor Marie Reilly, Karolinska Institute, Sweden; Professor Sir Mark Pepys, University College London; Professor Christian Brander and Dr Beatriz Mothe, Irsicaixa AIDS Research Institute HIVACAT, Spain; Dr Sarah Fidler, Imperial College London and Dr Joan Joseph, Hospital Clinic Barcelona, Spain;

KEY PUBLICATIONS
Hanke T. Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines.Expert Opin. Biol. Ther. 14: 601-616 (2014).

Borthwick B, Ahmed T, Ondondo B, Hayes P, Rose A, Ibrahimsa U, Hayton E-J, Black A, Bridgeman A, Rosario M, Hill AVS, Berrie E, Moyle S, Frahm N, Cox J, Colloca S, Nicosia A, Gilmour J, McMichael AJ, Dorrell L and Hanke T. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. MolTher 22:464-475 (2014).

Njuguna IN, Ambler G, Reilly M, Ondondo B,Kanyugo M, Lohman-Payne B, Gichuhi C, Borthwick N, Black A, Mehedi S-R, Maleche-Obimbo E, Chohan B, John-Stewart GC, Jaoko W and Hanke T. PedVacc 002: A phase I randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-infected mothers in Nairobi. Vaccine In press.