Vaccines by design

Excivion is developing novel vaccine solutions to epidemic and pandemic disease threats with a revolutionary new approach to rational vaccine design whereby the immune response to particular sites on an antigenic protein can be controlled to favour the generation of neutralising responses and to hinder the development of potentially harmful responses, such as those that foster infection with related pathogens (relevant to dengue, Zika, yellow fever and Japanese encephalitis), or that may cause autoimmune reactions. This new approach of 'vaccines by design' borrows well-established concepts of virtualisation and modelling from the science of drug design but takes a bold step beyond in the novelty of its approach.

Directed stimulation of neutralising immune responses

 

Harmful immune responses caused by natural infection have been known for many years, such as 'original antigenic sin', first coined to explain influenza virus pandemics (responsible for 20-40 million deaths in the 1918-1919 influenza H1N1 pandemic), but now recognized to be more generally relevant to other virus infections (notably the flaviviruses above). Original antigenic sin is a consequence of immunological memory whereby an encounter with a second strain of a particular virus recalls the production of futile non-neutralising antibodies that cross-react between the two strains of virus, to the detriment of the elicitation of neutralising antibodies against the second strain. The Zika pandemic is a game changer for vaccine developers, because it changes the rules about how we develop new vaccines against viruses in this family. Vaccines in the pre-zika era are all designed to provoke long lasting 'immunological memory’ whereby the immune system is programmed to recognize and remember an encounter with a vaccine, in a manner that prepares it for encounter ‘in the wild’ with a virus or bacterium. While this is essential for any new vaccine, in the case of Zika and the related dengue viruses, it is no longer ‘enough’. This is because, just like memories we hold in our minds, not all of them are good. What is needed is a vaccine that allows the immune system to ‘forget’ disease-enhancing immune responses, and that avoids boosting any underlying immune response capable of enhancement. Excivion has conceived a solution to this problem which is the basis of a pending patent. It is the first time a vaccine has been designed with amnesia in mind. There is much yet to prove, but this radical new approach holds great promise. Also, because all vaccine companies are starting from scratch with Zika, it sets a level playing field where a disruptive approach such as Excivion's can make rapid progress.

 

Navigating the complex epidemiology of flaviviruses

Flaviviruses, notably dengue, but possibly others, take original antigenic sin to a new level of sophistication by generating antibodies (against a first serotype) that actually assist infection with a second serotype of the virus. This is because flaviviruses can infect myeloid cells that have receptors for the 'tail' (Fc) part of an antibody molecule (FcRIIa). The Fc region of virion-bound antibodies provides a high-affinity ligand for the entry of the virion into myeloid cells (macrophages, dendritic cells) via FcRIIa, thereby enhancing infection and severity of disease. Given the complex epidemiology of mosquito-borne flavivirus infections, the potential exists for original antigenic sin to operate 'across diseases' (e.g. prior cases of dengue may foster zika virus infection). This concern is also relevant to new vaccines against these pathogens, which may, if not suitably designed, foster the epidemic spread of related flaviviruses by dint of original antigenic sin. New vaccines need to be designed to minimise the risk of homologous enhancement (where a vaccine would give rise, in some recipients, to the disease it is meant to prevent - e.g. by predisposing to severe dengue) as well as the risk of heterologous enhancement (e.g. where a vaccine against dengue could potentially enhance susceptibility of an individual or a population to zika virus infection). Excivion's vaccines are designed with the wisdom of hindsight in the post-zika era (i.e. since the pandemic emergence of zika in 2014-15) with these principles in mind, i.e. where safety against enhancement is an inbuilt design feature from the outset.

The benefits of vaccination

Vaccines remain the safest and most effective option for the control of infectious diseases, having saved countless lives. With suitable attention to safety in the rational design of new vaccines, this will continue to be true for many decades to come.