Final Report Summary - ADJSYN (Understanding how immunostimulant combinations in adjuvants synergise to enhance vaccine responses) NON-TECHNICAL SUMMARYFor more than 200 years, vaccines have been one of the most successful medical interventions to save lives and to protect against infectious diseases [1]. Millions of people have been saved from early death and disability from diseases like polio thanks to successful immunization programmes. Due to the effectiveness of a vaccine to protect against it, smallpox was eradicated in 1979 [2]. Vaccines deliver a killed or weakened pathogen, or pieces of it, intended to trigger an immune response that generates “memory” cells primed to recognise the same microorganism quickly in the future and ready to block any attempted re-infection by the same organism, or at least reduce illness. In the last few decades, advanced knowledge of immunology has revealed that there may be opportunities to develop more vaccines to help protect more people, and against a wider variety of illnesses. Some of these opportunities involve the use in the vaccine of a substance that enhances the immune response to the vaccine. Such substances are known as “adjuvants” (from the Latin word “adjuvare” meaning “to help”). Aluminium salts are the most common adjuvants in vaccines and have been used for over 80 years [3]. New classes of adjuvants allowed scientists to make vaccines more efficacious and thereby produce previously impossible vaccines. Scientists at GSK Vaccines have combined immunostimulants, creating “Adjuvant Systems” (AS). One of these Adjuvant Systems, AS01, is in several candidate vaccines in clinical development; including GSK’s candidate malaria vaccine [4-7], the candidate shingles vaccine [8], and the candidate tuberculosis vaccine [9]. AS01 combines two different adjuvants: 1) monophosphoryl lipid A, a non-toxic derivative of bacterial cellular wall; 2) QS-21, a compound belonging to the saponin family, which is extracted from the bark of the Quillaja saponaria tree These two compounds are prepared into a liposome, a small spherical particle made of lipid molecules [10].We have previously demonstrated that the memory response induced by vaccines containing the two adjuvants combined in AS01 is stronger than that prompted by vaccines containing MPL or QS-21 alone [11]. Recent advances in immunology showed that the events that happen in the first hours following vaccination may drive the generation of memory responses. Yet, little is known regarding what these events are when adjuvants such as AS01 are used. This project aimed to understand: 1) which are the early events after vaccination induced by AS01; 2) what is the added value of combining MPL and QS-21 in driving these events; 3) what is the impact of these events in generating a good memory response and, by consequence, in helping the vaccine protect against subsequent infections. To answer these questions, we used a combination of classical cellular immunology with computer-based studies. Using statistics, we showed that combining MPL and QS-21 in AS01 leads to many different kinds of effects on the local immune system, including many that are not observed when you use the two compounds singularly. We also described the events induced by vaccination with AS01 in the first hours after vaccination. We found that AS01 induces the activation of a specific type of immune cell called Natural Killer cell. In spite of their name, Natural Killer cells don’t necessarily kill cells. In contrast, they can be activated really quickly by vaccination with AS01 (within 4h in the mouse model used) and they are very important in promoting the memory response. In fact, we find that they are important also in promoting the protection from disease induced by vaccination. While most of our work is in mouse models, we can find hints of Natural Killer cells activation also in humans that are vaccinated with AS01-containing vaccines. Overall, our work sheds light on the early events happening after vaccination with AS01-containing vaccines. Three of such vaccines, against malaria, tuberculosis and shingles, are in advanced clinical tests, so this work is important in helping us to understand how they work and how they could be improved. In addition, we are providing new clues on how to identify patients that may not respond very well to vaccination. As a consequence, our work will be useful to patients, clinicians and vaccine developers to make sure that we can deliver safe and efficient vaccines for complex diseases, ultimately protecting more people from death and disability.1. World Health Organization. Immunization. 2015 [cited 07/07/2015; Available from: http://www.who.int/topics/immunization/en/.2. World Health Organization Media Centre. The Smallpox Eradication Programme - SEP (1966-1980). 2010 [cited 07/07/2015; Available from: http://www.who.int/features/2010/smallpox/en/.3. Coffman, R.L. A. Sher, and R.A. Seder, Vaccine adjuvants: putting innate immunity to work. Immunity, 2010. 33(4): p. 492-503.4. Kester, K.E. et al., Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis, 2009. 200(3): p. 337-46.5. Stoute, J.A. et al., A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med, 1997. 336(2): p. 86-91.6. Sun, P., et al., Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-gamma. J Immunol, 2003. 171(12): p. 6961-7.7. Rts, S.C.T.P. et al., A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med, 2012. 367(24): p. 2284-95.8. Lal, H., et al., Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med, 2015. 372(22): p. 2087-96.9. Leroux-Roels, I., et al., Improved CD4(+) T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine, 2013. 31(17): p. 2196-206.10. Garcon, N. and M. Van Mechelen, Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev Vaccines, 2011. 10(4): p. 471-86.11. Dendouga, N., et al., Cell-mediated immune responses to a varicella-zoster virus glycoprotein E vaccine using both a TLR agonist and QS21 in mice. Vaccine, 2012. 30(20): p. 3126-35.
