Henry Wellcome Building for Molecular Physiology
Alexander (Sandy) Douglas
DPhil, MRCP, DipPharmMed
I am an academic clinician and hold a Wellcome Trust Postdoctoral Fellowship for Clinicians (i.e. Career Development fellowship). I am also a Co-Investigator on the EPSRC funded Future Vaccine Manufacturing Research Hub (Vax-Hub) and hold an MRC grant to develop a novel rabies vaccine and carry out clinical trials.
My main interests are the development of efficient and scalable vaccine manufacturing processes, development of antibody-inducing vaccines against the rabies virus and sporozoite stage of malaria, and the development of vaccine thermostabilisation technologies.
In earlier work, I identified the potential of PfRH5 as an antigen capable of inducing highly potent strain-transcending neutralising antibodies against the disease causing blood-stage of Plasmodium falciparum and demonstrated that PfRH5-based vaccines could achieve in vivo protection against a virulent P. falciparum challenge. These vaccines are now in clinical trials.
Vaccine manufacturing process development
We have developed and exectured a plug and play process for GMP manufacture of adenovirus vectored vaccines. Developed in my laboratory, this process has been used on numerous vaccines and found to increase yields and decrease costs. It was successfully executed to GMP standards in 2019 as part of our rabies vaccine manufacturing work.
Many people do not realise that rabies kills around 50,000 people each year. One reason is that existing rabies vaccines require multiple doses, cold-chain storage and are moderately expensive. I am leading a project to manufacture and test in clinical trials an adenovirus-vectored rabies vaccine. In pre-clinical studies, a single low dose of the vaccine achieves protection against rabies challenge for over two years. The vaccine aims to become a cheap, single-dose tool suitable for mass pre-exposure rabies prophylaxis. It has recently entered Phase I trials in the UK and will be used in an upcoming clinical trial in a rabies endemic region.
In conjunction with the rabies vaccine work, we are carrying out a project to explore the best technologies for thermostabilising vaccines. The adenovirus vectored rabies vaccine is being used as our model vaccine. The thermostabilisation technology has potential to be applied to multiple human and veterinary vaccines, overcoming the challenges and cost of cold chain distribution.
Antibody targets on Plasmodium spp. sporozoites
Understanding of the mechanism of erythrocyte invasion by P. falciparum merozoites has yielded promising new vaccine targets like PfRH5. Sporozoites are in many ways more attractive vaccine targets than merozoites, but understanding of the mechanism of sporozoite invasion into hepatocytes is poor. I am seeking to identify sporozoite ligands and host receptors required for this invasion process, with the aim of developing interventions to prevent infection by disrupting their interactions.
Most candidate malaria vaccines targeting extracellular stages of the parasite require extremely high antibody concentrations to achieve efficacy. Recent clinical trials have shown that current adjuvant formulations are not capable of sustaining such levels for more than a few weeks. I have an interest in the development of protein subunit vaccine formulations capable of enhancing the long-term maintenance of high-level antibody titers.
A screen for Plasmodium falciparum sporozoite surface protein binding to human hepatocyte surface receptors identifies novel host-pathogen interactions
Segireddy RR. et al, (2020)
A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
Douglas AD. et al, (2019), Nature Communications, 10
Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components
Fedosyuk S. et al, (2019), Vaccine, 37, 6951 - 6961
Functional Comparison of Blood-Stage Plasmodium falciparum Malaria Vaccine Candidate Antigens
Illingworth JJ. et al, (2019), Frontiers in Immunology, 10
Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies
Alanine DGW. et al, (2019), Cell, 178, 216 - 228.e21