Most existing vaccines work by generating an antibody response. However, it is now clear that an antibody response is insufficient for protecting against many diseases; in these cases, a T cell-based immune response is also needed. The next wave of growth in the vaccine market is being driven by the development of a new generation of vaccines aimed at eliciting a greater balance between T-cell and B-cell responses.
The most relevant T-cell population for the clearance of intracellular pathogens and the elimination of tumor cells are cytotoxic CD8 T-cells. The best way to elicit a CD8 T-cell response against an antigen is to deliver the gene coding for that particular antigen.
A genetic vaccine contains a segment of DNA that encodes an antigen delivered to the body, either as naked DNA or within a viral particle. The body’s cells, usually muscle, then make the corresponding protein antigen.
In extensive studies, adenoviruses have been found to be one of the most potent vectors for the induction of CD8 T-cell responses in primates, including humans, while also inducing protective antibody responses. In addition to high immunological potency, its effectiveness as a vaccine requires high productivity and low levels of pre-existing neutralizing antibodies against the adenovirus vector. Human adenovirus vectors have previously suffered from anti-adenovirus antibodies frequently present in human serum. We have circumvented this problem by isolating and extensively characterizing a large number of adenovirus strains from chimpanzees. These highly-potent adenovirus vectors are not neutralized by antibodies present in humans and are capable of infecting and growing in approved human cell lines. These chimpanzee-derived adenovirus vectors can be used for numerous infectious diseases and in oncology.
We have developed a vaccination protocol involving heterologous prime-boost that exploits the high potency of adenovirus vectors as primers of T-cell and B-cell immune response, which can be boosted either by another vector or by recombinant proteins or peptides.
Following primary vaccine challenge, CD8 T-cells undergo expansion and contraction, and they form a primary memory population. When this population is exposed to a secondary challenge of the same vaccination (homologous boost; see the dashed line in the chart), another round of expansion and contraction, and the formation of a larger, secondary memory population occur. In contrast to a homologous booster vaccination, a CD8 T-cell antigen delivered in the context of a different vector (heterologous boost; see the solid line) drives greater expansion of the primary memory CD8 T-cells, resulting in a larger secondary population.
In human trials, we have shown that when using a Modified Vaccinia Ankara (MVA) vector as a booster, high levels of Effector Memory CD8 T-cells are induced. This phenotype was demonstrated to be associated with protection against viral infections, and it is the one induced by highly-efficacious vaccines like yellow fever and smallpox.
At ReiThera we have developed capabilities to produce MVA vectors expressing the gene of interest, to be used as booster vectors.
A pipeline of genetic vaccines to target diseases for which there is currently no effective prophylactic or therapeutic vaccines
Our long standing research in the field of Hepatitis C virus has shown that a vectored vaccine containing the NS viral antigens is able to stimulate robust T-cell responses that provided 100% protection in preclinical non-human primate models. We have also shown in human clinical studies that the strength of the vaccine-induced T-cell response is much higher than that observed in individuals who are able to spontaneously clear acute HCV infection. The efficacy of the prophylactic HCV vectored vaccine is currently under testing in a Phase II study (https://clinicaltrials.gov/ct2/show/NCT01436357) sponsored by the National Institutes of Health (NIH).
There is a consensus that for a prophylactic HIV vaccine stimulation of both arms of the response would be optimal, with antibody responses aimed at preventing initial infection and CD8+ T cell responses to control infection that breaks through the antibody barrier. Chimp adeno-based HIV vaccines were exploited at the University of Oxford with the aim of inducing protective CD8+ (killer) T cells focused on conserved regions of the HIV-1-proteome. The program includes 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.
A genetic vaccine eliciting balanced B and T-cell immune responses can address the need for a safe and effective prophylaxis against respiratory syncytial virus (RSV) infection, which is the most important cause of viral lower respiratory tract illness in infants and in the elderly worldwide. In collaboration with the Institute of Animal Health (IAH, UK) we have obtained strong pre-clinical evidence in a bovine model of B-RSV infection, that a vectored RSV vaccine can provide complete and safe protective efficacy. A Phase I clinical study of the vectored RSV vaccine showed a good safety and immunogenicity profile in both young and old adults, paving the way to further clinical development, currently conducted by GSK.
By a long standing collaboration with the University of Oxford, we have been involved in the preclinical and clinical development of vectored vaccines containing different malaria antigens with the aim of generating multi-gene vaccines targeting the various stages of the parasite lifecycle.
The 2014 outbreak in equatorial African countries accelerated the clinical development of a candidate vector-based Ebola vaccine that we developed in collaboration with the Vaccine Research Centre at the National Institutes of Health (NIH). Results from Phase I clinical trials for ChAd3-ZEBOV, conducted by GSK in collaboration with the US National Institute of Allergy and Infectious Diseases (NIAID), showed that the vaccine is safe and immunogenic in humans. To cope with the sudden need of several hundreds of thousands doses, ReiThera’ GMP manufacturing facility scaled up the production process of the vectored vaccine in a very short time.
Rabies is the most fatal of all infectious diseases and still remains a major health problem in developing countries, causing tens of thousands deaths each year. Rabies vaccines for humans are available but their use is limited due to costs and complicated schedule. Considering the severity of rabies and its continued high incidence, development of an improved vaccine for rabies is warranted. Such a vaccine would have to provide sustained protection after a single dose application. Therefore there was a strong rationale to exploit the simian Adeno vector platform in order to comply with the features of an improved rabies vaccine. ReiThera is advancing an adeno-vectored vaccine expressing the Rabies G protein from preclinical studies to the clinic.