Developing a Vaccine for Alzheimer’s Disease
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Vaccines have long been used as a preventative measure against several infectious diseases, and in more recent years are being developed to treat certain types of cancer. Interest is now growing in the use of vaccines to prevent neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). A vaccine capable of blocking the formation of AD- and/or PD-linked proteins could have the potential to significantly delay or stop the onset of the disease.
The Institute for Molecular Medicine (IMM), recently announced the licensing of MultiTEP – a universal vaccine platform technology – to Nuravax. The platform has shown promising preliminary results in preclinical studies, overcoming some of the challenges of activating aged immune systems. To learn more about MultiTEP, results so far and how the platform could be applied to other neurological indications and diseases, Technology Networks spoke with Roman Kniazev, chief executive officer at Nuravax.
Anna MacDonald (AM): Why is Alzheimer’s disease such an extraordinarily complex condition to cure?
Roman Kniazev (RK): Alzheimer’s disease is a complex and multifactorial disease, like obesity and cancer, involving genetic and environmental risk factors that together lead to the progressive accumulation of two hallmark pathologies: β-amyloid plaques (Aβ) and neurofibrillary tangles (tau). There are many different hypotheses, but most scientists and medical doctors agree that Aβ and tau participate in AD pathology (inflammation, oxidative stress, neurodegeneration). Once pathology begins, it becomes virtually impossible to stop and its complexities have left scientists debating its root causes.
It is irrefutable that interactions between Aβ and tau are major drivers of disease pathology. The pathology could start as early as 35-45 years old, but a person could experience the first signs of cognition impairment many years, even decades, later. Up until now, AD therapeutics have been focused on treating pathology after the disease has taken hold, but we think prevention is the most effective strategy to stop or at least delay the onset of AD by 10 to 20 years.
AM: So, the best way to cure a disease is to avoid its onset from the beginning. A vaccine is the perfect tool. Can you explain Nuravax’s approach to vaccines and how MultiTEP can overcome some of the challenges encountered by other companies?
RK: Nuravax is using a unique type of vaccine that is based on the universal MultiTEP platform technology developed at IMM. This platform stimulates memory and naïve T helper cells that in turn activate B cells to produce antibodies at much higher rates than vaccines currently used in clinical trials. With large amounts of antibodies produced, the aim is to prevent/inhibit Aβ and/or tau aggregations and halt or at least delay the onset of disease.
Given that up to 0.5% of antibodies generated outside of the brain can cross the blood-brain barrier, the immune system must be strongly stimulated to produce very large amounts of antibodies for Alzheimer’s vaccines to work. Nuravax’s vaccine does this with its three components:
o The proprietary MultiTEP carrier platform, containing short segments of 12 different promiscuous peptides (fragments) linked together, activates a broad repertoire of T helper cells and significantly increases antibody production by B cells;
o Three copies of the Aβ and/or tau toxic Alzheimer’s disease target epitopes that provide a signal to B cells to produce high titers of antibodies to these molecules;
o An immune system stimulator (adjuvant), superior to its competitors, gives a super boost to antibody generation.
Our proprietary MultiTEP, licensed from IMM, can produce vaccines that trigger the cellular component of the immune system, so called memory T helper cells, without inducing antibodies to the platform itself.
o MultiTEP-based vaccines were able to elicit antibody production across the diversity of immune system genes of all the primates studied.
o Our vaccines did not induce antibodies specific to epitopes incorporated in MultiTEP and generated only low levels of antibodies against conformational epitopes of the platform itself, meaning that patients could continue to receive our vaccines as yearly boosters as opposed to AD vaccines that utilize big carriers that are recognized and quickly cleared by the organism.
AM: Why pursue different approaches (DNA and recombinant protein)? What’s the benefit of this multi-pronged attack?
RK: DNA vaccination represents a unique alternative method of immunization and has properties that may be advantageous in developing a range of vaccines against different diseases, including Alzheimer’s. A major advantage of DNA vaccination is the ability to activate innate immunity without an adjuvant and induce adaptive humoral and cellular immune responses. DNA vaccines have strong advantages: a) low cost, b) easy storage, c) simple requirements for transportation.
However, this vaccination strategy has not achieved widespread acceptance for human use mostly due to their low immunogenicity in clinical trials related to the delivery of the vaccine into the nucleus. Recently, this has been changed, and the first preventive DNA vaccine delivered by a PharmaJet device has been approved for COVID-19 in India. We are planning to use the same device for the delivery of our DNA vaccines against pathological amyloid, tau and a-synuclein.
Nevertheless, to induce high titers of antibodies in humans at risk of AD we may also need a DNA prime/protein boost regimen. It will allow us to prime people with a DNA vaccine against amyloid and come back and do yearly vaccination with a recombinant adjuvanted protein vaccine targeting Aβ or tau or both simultaneously.
AM: Can you share your preliminary findings from preclinical studies?
RK: MultiTEP has been designed to activate immune response genes not only in the young and middle-aged but also in elderly people with an impaired immune system (so called immunosenescence or immune tolerance). Thus, we tested the effect of our vaccines in animal models showing this same condition. In particular, using the MultiTEP technology we developed vaccines that overcome immune tolerance and elicit extremely high levels of antibodies in vaccinated mouse models of Alzheimer’s and in aged non-human primates with immune systems like humans. With large amounts of antibodies produced in vaccinated people at risk of Alzheimer’s, we could stop amyloid aggregations and plaque formation as well as accumulation of pathological tau delaying the disease.
Collectively, our published and unpublished data argue that all vaccines based on MultiTEP technology induced production of high titers of antibodies in inbred mice (including mouse models of AD and PD), as well as outbred rabbits, and non-human primates with immune systems like humans.
The therapeutic efficacy of AV-1959R and AV-1980R was tested in special transgenic mouse models of AD. These transgenic mice resemble early and later stages of disease progression, similar to those observed in patients with clinically diagnosed AD.
For example, PS19 transgenic mice develop tau pathology within specific brain regions. Thus, we analyzed the impact of vaccination with adjuvanted AV-1980R on tau pathology and the relationship between this pathology and behavioral improvement.
The AV-1980R vaccine induced extremely high titers of antibodies that recognized all forms of pathological misfolded tau (e.g., neurofibrillary tau tangles and plaque-associated dystrophic neurites) in AD brain sections. Vaccination also improved the behavior of PS19 tau transgenic mice. Briefly, novel object (NOR) and novel place recognition (NPR) tests are based on the spontaneous tendency of rodents to spend more time exploring a novel object and novel place than a familiar one. The data showed that vaccination with AV-1980 resulted in a significant increase in the exploration of a non-familiar object and object located in a novel place as indicated by the increased recognition index compared with control mice. Thus, vaccination significantly reduces tau pathology and prevents age-related motor and cognitive deficits in PS19 mice meaning that AV-1980R immunotherapy represents an effective strategy for AD immunotherapy. Based on this and other studies we recently completed, including IND-enabling studies (paper submitted), we are planning to apply to the FDA and obtain clearance for Phase 1 clinical trials with AV-1980R.
We also designed a combinatorial dual vaccination approach to concurrently target both Aβ and tau pathologies in Tau22/5xFAD (T5x) biogenic mice.
The T5x mouse model exhibit accumulation of aggregated Aβ that accelerated the accumulation of misfolded and hyperphosphorylated tau in the brain of aged mice. Therefore, these bigenic mice developed highly aggressive Aβ and tau pathology representing the most valuable model for testing of our dual vaccine immunogenicity and efficacy.
The bigenic mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau- specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Vaccination led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ, within the brains of mice. Therefore, AV-1959R and AV-1980R formulated with a strong adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both hallmark pathologies of AD in bigenic mice.
Our tau protein vaccine, AV-1980R, induces an average antibody titer of 1: 256,000 after 3 immunizations also in aged non-human primates with an immune system like humans (paper submitted).
Taken together, all these findings warrant further development of this vaccine technology for ultimate testing in human AD. Of note, we are planning to complete IND enabling studies and request FDA clearance for Phase 1 trials of the dual vaccine in 2022.
AM: Do you plan to apply/study Nuravax’s MultiTEP technology on other neurological indications? Could this technology also be applied to a wider range of diseases?
RK: Yes, our proprietary vaccine platform is universal, and it could be used for the development of vaccines for various neurological indications. MultiTEP is especially helpful in CNS diseases. And yes, this platform could be used for the development of vaccines against other diseases too. In our pipeline, we have a Parkinson’s vaccine and vaccines against various tauopathies. Importantly, we should have relevant non-invasive biomarkers to initiate preventive vaccinations of middle-aged and elderly people at risk of disease.
AM: COVID-19 has sped up vaccine technology development worldwide. Will Nuravax benefit from this situation? What are the upcoming milestones for the company?
RK: Noticeably, COVID-19 has sped up vaccine technology development worldwide. Vaccines are the future of AD therapy and Nuravax is at the forefront of this development effort. We believe that if we can prevent or slow the accumulation of pathological Aβ, tau, or both with a vaccine administered before the onset of disease, we can prevent or delay it significantly.
Thus, IMM will continue to focus on the development of new breakthrough products based on MultiTEP, while Nuravax is poised to change the landscape of neurodegenerative disease prevention. The company will onboard experts in clinical development who will help to expedite FDA approval of preventive vaccines for AD, Down Syndrome, PD and various tauopathies. Simultaneously, Nuravax is working to attract various strategic partners including pharmaceutical companies developing vaccines for CNS diseases.
Nuravax aims to create a new segment in the market for the treatment of AD and PD. This segment requires the combination of a safe and highly immunogenic vaccine for asymptomatic (healthy) people at risk of AD and PD based on a set of non-invasive and accurate disease biomarkers. The company estimates the size of this market in the United States as ~40 million asymptomatic pre-AD people annually.
Roman Kniazev was speaking to Anna MacDonald, Science Writer for Technology Networks.
