Natural Killer cells as effectors of vaccine-induced immunity
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: Infectious and Tropical Diseases
Abstract
Vaccination is the most sustainable and cost-effective way to reduce the global burden of many infectious diseases. New vaccines are urgently needed for many infections including malaria, HIV and TB but it has proven very difficult to make efficacious vaccines against these infections. Currently, the only way to test these vaccines is to carry out clinical trials where many hundreds or thousands of people are vaccinated and then wait to see if they become infected or not. If the vaccines don?t work - as has been the case recently for several malaria, HIV and TB vaccines - then a lot of time and money has been spent but we are no nearer to understanding what is going wrong. One way to speed up the process of vaccine development is to identify ?correlates of protection?. In other words, to identify immune responses which, when present, are good indicators that the person is protected. For many vaccines, the presence in the blood of antibodies to the vaccine organism provides evidence that the person is protected but, for diseases such as malaria, HIV and TB, antibodies are a poor indication of protection and other responses are required.
The purpose of this research is to evaluate the predictive value of potential new correlates of protection, namely the ability of cells called T cells to make a molecule called IL-2 and the ability of natural killer (NK) cells to respond to IL-2 by making IFN-gamma and killing infected cells. We suspect that these responses correlate better with protection than do existing markers. We will test this by comparing immune responses before and after vaccination to see if T cell and NK cell responses have been induced, see how long the responses last after vaccination, and see if the presence of these responses is required for protection and is a good indicator of protection. A large part of this work will be carried out at the MRC Laboratories in The Gambia, West Africa. In 1984, a vaccine for hepatitis B was introduced in The Gambia and has been highly effective at preventing hepatitis and liver cancer. Our preliminary data indicate this vaccine induces both IL-2 producing T cells and IFN-gamma-producing NK cells and we now want to see if these responses are correlated with long term protection against hepatitis B infection. If so, we will investigate how these responses can be most efficiently induced by vaccination.
The purpose of this research is to evaluate the predictive value of potential new correlates of protection, namely the ability of cells called T cells to make a molecule called IL-2 and the ability of natural killer (NK) cells to respond to IL-2 by making IFN-gamma and killing infected cells. We suspect that these responses correlate better with protection than do existing markers. We will test this by comparing immune responses before and after vaccination to see if T cell and NK cell responses have been induced, see how long the responses last after vaccination, and see if the presence of these responses is required for protection and is a good indicator of protection. A large part of this work will be carried out at the MRC Laboratories in The Gambia, West Africa. In 1984, a vaccine for hepatitis B was introduced in The Gambia and has been highly effective at preventing hepatitis and liver cancer. Our preliminary data indicate this vaccine induces both IL-2 producing T cells and IFN-gamma-producing NK cells and we now want to see if these responses are correlated with long term protection against hepatitis B infection. If so, we will investigate how these responses can be most efficiently induced by vaccination.
Technical Summary
The aim of this programme is to explore the potential for Natural Killer (NK) cells to contribute to the effector phase of adaptive (acquired) immune responses to infection following vaccination. We have recently shown that NK cell cytokine and cytolytic activities are markedly enhanced after vaccination as a result of induction of antigen-specific, IL-2 secreting CD4+ T lymphocytes. Upon subsequent exposure to the pathogen, T cell-derived IL-2 synergises with signals from myeloid accessory cells (including IL-12, IL-18, IFN-alpha and contact-dependent costimulation) to induce extremely potent and rapid activation of NK cells. The aims of this programme are to determine the kinetics of induction and duration of NK responses post vaccination, the cellular and molecular requirements for NK cells to be activated post-vaccination and whether NK cells contribute to vaccine efficacy.
The programme comprises three strands:
1. Observational studies in humans, in the UK and The Gambia undergoing immunisation with licensed vaccines, to characterise NK cell and CD4+ T cell IL-2 responses before, during and after vaccination, to determine whether NK / CD4+ T cell responses vary between individuals or with age at vaccination and to determine the longevity of the NK/CD4+ T cell responses and the effects of boosting.
2. A cohort study with nested case-control study, in The Gambia, to determine the prevalence, magnitude and longevity of NK and CD4+ T cell responses to hepatitis B virus (HBV) in individuals who were HBV vaccinated at birth, to correlate NK and T cell responses with humoral vaccine responses and with indicators of natural HBV infection, to determine whether NK/T cell responses correlate with protection against natural HBV infection, and to explore potential associations between NK/T cell responses, genetic, physiological and nutritional parameters.
3. Experimental studies in mouse models of infection to characterise NK cell responses to pathogens before and after infection and/or vaccination and to compare resistance to infection between intact mice and mice in which NK cells have been depleted after vaccination.
NK and T cell responses will be assessed by flow cytometry, by functional in vitro assays (e.g. cytotoxicity) and (in mice) by experimental infection. We expect the work to provide new assays and new correlates of protection for rapid evaluation of vaccine efficacy, screening of new antigens and adjuvants, optimising dosing schedules and determining duration of protection. Where appropriate, this may lead to vaccines being specifically designed to induce NK responses.
The programme comprises three strands:
1. Observational studies in humans, in the UK and The Gambia undergoing immunisation with licensed vaccines, to characterise NK cell and CD4+ T cell IL-2 responses before, during and after vaccination, to determine whether NK / CD4+ T cell responses vary between individuals or with age at vaccination and to determine the longevity of the NK/CD4+ T cell responses and the effects of boosting.
2. A cohort study with nested case-control study, in The Gambia, to determine the prevalence, magnitude and longevity of NK and CD4+ T cell responses to hepatitis B virus (HBV) in individuals who were HBV vaccinated at birth, to correlate NK and T cell responses with humoral vaccine responses and with indicators of natural HBV infection, to determine whether NK/T cell responses correlate with protection against natural HBV infection, and to explore potential associations between NK/T cell responses, genetic, physiological and nutritional parameters.
3. Experimental studies in mouse models of infection to characterise NK cell responses to pathogens before and after infection and/or vaccination and to compare resistance to infection between intact mice and mice in which NK cells have been depleted after vaccination.
NK and T cell responses will be assessed by flow cytometry, by functional in vitro assays (e.g. cytotoxicity) and (in mice) by experimental infection. We expect the work to provide new assays and new correlates of protection for rapid evaluation of vaccine efficacy, screening of new antigens and adjuvants, optimising dosing schedules and determining duration of protection. Where appropriate, this may lead to vaccines being specifically designed to induce NK responses.
