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 first positioned as a complement to the current seasonal vaccine, adding efficacy and value to one of the incumbents. The improvement in efficacy should be seen as a driver to increase the overall coverage of the influenza vaccine. It may also be used alone in a pandemic or pre-pandemic setting.
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.
VTP-100, our lead candidate, MVA encoding NP+M1, has undergone 6 clinical trials in over 400 subjects. 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. VTP-100 has already demonstrated in initial trials an ability to generate a strong T-cell response that matches or exceeds those found in persons who are protected in each flu season.
Vaccitech has now manufactured this influenza vaccine at scale together with its partners, and is beginning two Phase 2b trials. Trial Flu 010 will test the ability of VTP-100 to protect healthy adult study participants from a challenge with the A/Belgium/4217/2015 (H3N2) influenza virus strain. Additionally, trial Flu 009 has commenced in Australia with over 2,000 subjects, including a cohort over the age of 65, to look at the effect of VTP-100 on influenza-like illness.
- 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 Vaccine Expressing Conserved Influenza A Antigens Mol Ther. 2014
- Folegatti P.M. et al., Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line. MDPI Vaccines, 2019
Clinical trial references.
FLU008 – 2017-001104-30 (EudraCT)
FLU009 – NCT03880474 (ClinicalTrials.gov)
FLU010 – NCT03883113 (ClinicalTrials.gov)
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 prostate 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 oncofetal antigen 5T4, in vaccine VTP-800, with breakthrough checkpoint inhibitors that are now licensed. Our Phase 1 ChAdOx1 + MVA study enrolled 40 subjects and had data presented at ASCO 2018. A Phase 2 trial is underway, evaluating VTP-800 in combination with the checkpoint inhibitor Opdivo, in metastatic patients and for those 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
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 likely require the addition of checkpoint inhibitors to the vaccine regimen. The vaccine is in GMP manufacture with clinical trials in Q1 2020.
There is usually no cure for chronic HBV, due to the persistence of cccDNA (covalently closed circular DNA), which results in renewed viral production 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 limited in the use of T cell approaches due to non-recognition of presented peptides, T cell exhaustion 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 GMP manufacture with clinical trials planned in Q4 2019.
Middle East Respiratory Syndrome
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 has entered a Phase 1 clinical trial at Oxford University. 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 a MERS vaccine through Phase 2 studies to the establishment of a human vaccine stockpile.
The licensed, live-attenuated VZV vaccine (Zostavax) has a good level of efficacy in people aged up to 70 years, but its duration may not be sufficient to provide lifelong immunity.
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°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 individuals over the age of 65. Remarkably, there was no decline in immunogenicity in the older age group and T cell responses were maintained at 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.