Influenza prophylactic in elderly: Phase 2
Prostate CA therapeutic with checkpoint inhibitor: Phase 1
MERS prophylactic: GMP Product
HPV therapeutic: Preclinical
HBV therapeutic: Preclinical
Cancer (indication undisclosed): Preclinical
Influenza is a highly infectious viral disease that can lead to hospitalisation and death and is incredibly costly to health systems.
Seasonal flu typically causes more than 200,000 hospitalizations and 36,000 deaths every year in the United States alone, according to the U.S. Centers for Disease Control and Prevention.
While a yearly flu shot provides some protection, subtypes not covered by the vaccine can emerge rapidly. This phenomenon was evident in the 2009 spread of the H1N1 (“swine flu”) subtype that killed an estimated 151,700 to 575,400 people worldwide. The Vaccitech universal flu vaccine will be positioned as a complement to the current seasonal vaccine, adding efficacy and value to one of the incumbents. The increase in efficacy should be seen as a driver to increase the overall coverage of the influenza vaccine.
The Vaccitech vaccine is designed to protect against all strains of influenza A virus; including swine flu, avian (bird) flu, and human flu.
In influenza seasons those patients with the highest T-cell meditated response (top 20-30%) have been protected from disease. The vaccine is capable of inducing this level of T-cell response against all strains of the influenza A virus.
Our lead candidate, MVA encoding NP+M1, has undergone 5 clinical trials in over 150 patients. Nuclear protein and Matrix Protein 1 are antigens in the matrix underneath the viral capsule that are conserved across all families of influenza A virus. The vaccine has two very important qualities that have been demonstrated in initial trials. Firstly, it generates a strong T-cell response that matches or exceed those found in patients who are protected in each flu season. Secondly it also generates an antibody response greater than the response produced by the standard influenza alone.
Vaccitech has now manufactured this Influenza Vaccine at scale together with its partners, and is beginning a Phase 2 trial of 2,000 subjects over the age of 65 to show an effect on influenza-like illness. The trial will run at six sites in the UK over a two-year period.
Clinical trial references
- Berthoud, T.K., et al., Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A vaccine, MVA-NP+M1. Clin Infect Dis, 2011.
- Lillie, P.J., et al., A preliminary assessment of the efficacy of a T cell-based influenza vaccine, MVA-NP+M1, in humans. Clin Infect Dis, 2012.
- Antrobus, R.D., et al., A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP+M1 in adults aged over 50 years. PLoS One, 2012.
- Lambe T., et al., Immunity Against Heterosubtypic Influenza Virus Induced By Adenovirus And MVA Expressing Nucleoprotein And Matrix Protein-1. Sci Rep. 2013
- Powell T.J., Examination of Influenza Specific T Cell Responses after Influenza Virus Challenge in Individuals Vaccinated with MVA-NP+M1 Vaccine. PLoS One. 2013
- Mullarkey, C.E., et al., Improved adjuvanting of seasonal influenza vaccines: preclinical studies of MVA-NP+M1 coadministration with inactivated influenza vaccine. Eur J Immunol, 2013.
- Antrobus, R.D., et al., Coadministration of seasonal influenza vaccine and MVA-NP+M1 simultaneously achieves potent humoral and cell-mediated responses. Mol Ther, 2014
- Hayward, A.C., et al., Natural T Cell-mediated Protection against Seasonal and Pandemic Influenza. Results of the Flu Watch Cohort Study. Am J Respir Crit Care Med, 2015
- Antrobus R.D. et al., Clinical Assessment of a Novel Recombinant Simian Adenovirus ChAdOx1 as a Vectored VaccineExpressing Conserved Influenza A Antigens Mol Ther. 2014
Clinical trial references.
FLU007 – 2017-001103-77
FLU008 – 2017-001104-30
Prostate cancer is the most common cancer in men. It represents 26% of all male cancer diagnoses in the UK.
Prostate cancer is generally a disease of old age (and therefore increasing in prevalence), with only one in four new diagnoses made in men under 65.
The usual method of diagnosis is routine PSA (prostate specific antigen) testing followed by biopsies. The majority of cancers are diagnosed at an early stage. Local prostate cancer is often managed by active surveillance, surgery, brachytherapy (insertion of radio-therapeutic beads) castration (chemical or surgical). In later stage and metastatic disease, chemotherapy in often employed. There is a licensed vaccine for metastatic prostate cancer (Provenge), and many companies are designing cancer vaccines for various stages of the disease. The Vaccitech approach is to use the combination of ChAdOx1 and MVA, both encoding 5T4, and to combine these with the breakthrough product checkpoint inhibitors that are now licensed. Our phase 1 ChAdOx1 + MVA study has enrolled most of the 48 planned subjects, and our Phase 2 trial, planned for late 2017, will use the vaccination in combination with the checkpoint inhibitor Opdivo in both metastatic and for patients with intermediate risk cancer undergoing prostatectomy.
Redchenko, I., et al., Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination with PD-1 mAb in a mouse model of prostate cancer. Cancer Immunol Immunother. 2016
Clinical trial references.
VANCE – 2014-002990-12
Middle East Respiratory Syndrome
MERS is a viral respiratory disease caused by a novel coronavirus first identified in Saudi Arabia in 2012.
Coronaviruses are known to cause diseases ranging from the common cold to Severe Acute Respiratory Syndrome (SARS).
Typical MERS symptoms include fever, cough and shortness of breath. Pneumonia is common, but not always present, and approximately 35% of reported patients with MERS have died. Although the majority of human cases of MERS have been caused by transmission in health care settings, evidence suggests that dromedary camels are a reservoir for MERS-CoV, and a source of MERS infection in humans. Health care associated outbreaks have occurred in several countries, with the largest outbreaks seen in Saudi Arabia, United Arab Emirates, and the Republic of Korea.
Vaccitech has licensed the ChAdOx1 vaccine from the Jenner Institute, and this vaccine is capable of inducing antibodies to a level which are protective in animal models.
The vaccine has now been manufactured according to GMP practice and is entering a Phase 1 clinical trial at Oxford University in the coming months. MERS is an emerging infection, which has been recognized by the Coalition for Epidemic Preparedness Innovation as one of three major pathogens upon which to focus, and Oxford University has a pending proposal to advance the Vaccitech-owned vaccine through Phase 2 studies to the establishment of a human vaccine stockpile.
Alharbi, N.K., et al. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine. 2017
Shingles is a painful recurrence of varicella zoster virus (VZV, or chickenpox), that markedly increases in frequency with age.
The licensed, live-attenuated VZV vaccine (Zostavax) has a good level of efficacy in people aged up to 70 years, but the duration of may not be sufficient to provide lifelong immunity.
In people over 70 years (the NHS recommendation for use), vaccine efficacy declines markedly. Thus, there is a narrow age window at which to vaccinate in order to achieve maximum efficacy. The adjuvanted protein vaccine being developed by GSK can be given to immunocompromised individuals, and in a recent phase III study demonstrated extremely high efficacy in the over 50 age group. However, this highly reactogenic vaccine requires two doses. Ideally, a shingles vaccine would require only one dose with minimal side effects after vaccination, be safe in the immunocompromised, be safe in the immunocompromised, and provide high levels of efficacy over extended time.
A replication-deficient simian adenoviral vectored (SAV) vaccine expressing the glycoprotein E antigen of VZV can provide these desired characteristics. Recombinant replication-deficient SAVs such as the Vacitech proprietary ChAdOx1 are now in development for a number of vaccines, and were chosen by the WHO as a platform technologies for rapid development of novel vaccines against emerging pathogens. In addition to a highly acceptable safety profile, induction of protective immune responses after a single dose, and durably immunity, SAV vaccines can be manufactured extremely efficiently at large scale, and stored at 4 degrees C.
Shingles can only develop in individuals previously infected with VZV; normally immune responses are able to keep the infection in check to prevent the virus from reactivating.
With age, the T cell and other immune responses decline to the point at which the low level latent infection is no longer well controlled, resulting in shingles. Therefore an effective anti-shingles vaccine must boost the existing T and B cell responses back to protective levels, which will then be maintained over time. The SAV-vaccine vector ChAdOx1, licensed to Vaccitech has already demonstrated the ability to boost pre-existing cellular immunity following a single dose in a human influenza studies, including 24 individuals over the age of 50. Remarkably, there was no decline in immunogenicity in the older age group and T cell responses were maintained at a high levels following vaccination. We have now constructed a vaccine in ChAdOx1 using the same surface protein as the highly efficacious GSK vaccine (glycoprotein E), and have shown similar immunonogencity in mice. However, our vaccine has the advantage of low reactogencicity, one dose needed instead of two, and ease of manufacture.
There are between 250-350 million chronic HBV patients at risk for cirrhosis or hepatocellular carcinoma (HCC), which is the most common type of primary liver cancer in adults and the second leading cause of cancer mortality worldwide.
There is usually no cure for chronic HBV, due to the persistence of cccDNA (covalently closed circular DNA), which results in renewed viral produc- tion after cessation of antiviral therapy.
Thus, treatment is for life with rare spontaneous remission. Complete clearance of hepatitis B is associated with a CD8+ T cell response, but progress is lim- ited in the use of T cell approaches due to non-recognition of presented peptides, T cell exhaus- tion or other local related immune suppression activity.
The Vaccitech antigen insert is a multigenic construct based on group C Hepatitis B viruses developed in the laboratory of Professor Eleanor Barnes at Oxford University. The approach is to use the ChADOx1 vector boosted by an MVA construct containing the same HBV genes. Our approach also envisions the use of concomitant immune modulation during the T cell induction. The vaccine is in late pre-clinical development with GMP manufacture planned in 2018.
Human papillomavirus is the most common sexually transmitted virus, and persistent infection results in a variety of pre-cancerous lesions as well as cancer of the cervix, anus, and head and neck.
Work on a novel vaccine at Oxford University by Professor Lucy Dorrell with ChAdOx and MVA using key regions of multiple viral genes has shown robust immunogenicity in mice, and protection in a mouse tumour model.
This multigenic construct is based on a wider array of strains and antigens than other therapeutic HPV vaccines being developed. Clinical conditions that can be treated with the vaccine alone include cervical intraepithelial neoplasia and anal intraepithelial neoplasia. The use of the vaccine in adults with cancer will require the addition of checkpoint inhibitors to the vaccine regimen. The vaccine is in final phases of stability testing with GMP manufacture to start in late 2017.