Bilthoven, The Netherlands, 6 October 2022 – CEPI, the Coalition for Epidemic Preparedness Innovations, and Dutch vaccine clinical development and manufacturing organization Intravacc, today announced the latest funding award under CEPI’s US$200m programme to advance the development of vaccines that provide broad protection against SARS-CoV-2 (including its variants) and other Betacoronaviruses.

CEPI will provide seed funding of up to US$4.8 million to Intravacc—a world leader in translational research and development of preventive and therapeutic vaccines—to advance the development of a broadly protective Betacoronavirus vaccine candidate, which can be delivered intranasally.

CEPI’s funding will support preclinical development and testing of Intravacc’s subunit vaccine candidate (Avacc 101), which is based on its Outer Membrane Vesicle (OMV) platform.

This technology has the potential to be rapidly adapted to address outbreaks of disease caused by emerging Betacoronavirus strains and variants, and also to protect against pre-emergent Betacoronaviruses (ie, before they “spillover” from animals to infect humans). Specifically, the Avacc 101 vaccine candidate will be designed to provide broad protection against SARS-CoV-1, SAR-CoV-2, and MERS-CoV. This platform will enable presentation of universal Spike molecules and will include “epitopes” that can also elicit T-cell responses.

Unlike the COVID-19 vaccines currently in use, this candidate will be delivered intranasally. This method of administration could help to produce the mucosal immunity needed to block viral infection thereby reducing person-to-person transmission.
 

Enabling equitable access

CEPI is committed to the principle of equitable access to the vaccines it funds. Under the terms of the funding agreement, Intravacc has committed to achieving equitable access to the outputs of this project, in line with CEPI’s Equitable Access Policy.
 

Dr Richard Hatchett, CEO of CEPI said:
“The latest waves of Omicron subvariants in the US, UK, Europe and elsewhere show that SARS-CoV-2 still poses a serious threat to a still fragile global recovery. To secure the gains we’ve made, we must continue to develop vaccines that provide broad protection against these variants to mitigate the need for regular variant boosters, and which can also provide protection against other, more lethal, coronavirus threats including MERS-CoV. Investing in, initiating the development of, and enabling equitable access to broadly protective coronavirus vaccines should be an integral part of the world’s long-term strategy out of the COVID-19 pandemic and defence against future threats.”
 

Dr. Jan Groen, CEO Intravacc said:
“This is the real beginning of a new era for intranasal vaccines. Teaming up with CEPI is a big step forward: from ‘best alone’, to ‘better together’ In this way, we can leverage Intravacc’s OMV platform for the vaccine the world so desperately needs.”

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Bilthoven, The Netherlands, 5 October 2022 – Intravacc, a world leader in translational research and development of preventive and therapeutic vaccines, today announced that it has been awarded a contract with base and options that may total US$14.6 million from the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), for the development of a prophylactic intranasal  vaccine against Neisseria gonorrhoeae (NG). Gonorrhea is a sexually transmitted disease caused by the NG bacteria. Intravacc will develop a prophylactic vaccine based on its proprietary outer membrane vesicles (OMV) platform technology.

The NG vaccine, called NGoXIM, is based on gonococcal OMVs combined with sustained-release microspheres containing recombinant human IL-12, and will be administered intranasally. Proof-of-concept studies with NGoXIM have already shown the vaccine to be effective in animal models, inducing a potent, lasting, and cross-protective immune response. Intravacc will develop a complete production process for NGoXIM to generate vaccine batches under Good Manufacturing Practices. The company will work towards a non-clinical toxicity (TOX) and Clinical Trial Material batch to execute a Phase I study in healthy adults, investigating the safety of the vaccine and generating efficacy data. The IL-12 containing microspheres called GneX12 will be developed and produced by Therapyx Inc.

Gonorrhea

Gonorrhea is the second most common bacterial infectious disease in the US, with a reported incidence of more than 300,000 cases per year. Due to under-reporting and asymptomatic disease course, the true incidence is believed to be more than double the reported incidence. NG, a gram-negative aerobic 0.6–1.0 µm bacteria, is the cause of this sexually transmitted disease. Currently there is no effective gonorrhea vaccine available, and the disease is known to be contracted repeatedly without apparently developing protective immunity. In addition, antibiotic resistance is increasingly common for this bacterium. Gonorrhea is on the WHO high-priority list of antimicrobial resistant bacteria.

The project is funded by Federal funds from the National Institute of Allergy & Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93022C00058.

Dr. Jan Groen, Intravacc’s CEO, says:
“Together with our sub-contractor Therapyx, we are honored that NIH and NIAID have awarded us this contract, allowing both of us to demonstrate the safety and tolerability of our intranasal gonorrhea vaccine candidate, NGoXIM (Avacc 11®).”

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Bilthoven, the Netherlands, 12 September 2022 – Intravacc, a world leader in translational research and development of preventive and therapeutic vaccines, today announced additional favorable preclinical and toxicology data for Avacc 10®, the company’s SARS-CoV-2 intranasal candidate vaccine. These results demonstrate a reduction in upper respiratory tract viral load, broad cross protection against circulating variants of concern, and a good safety profile, allowing progression towards a phase I clinical study.

Dr. Jan Groen, Intravacc’s Chairman & CEO, comments:
“Based on our additional pre-clinical data, Avacc 10® has the potential to reduce the spreading of the virus as well as providing broad protection against circulation variants. Combined with the favorable toxicological safety data, this puts us a good position for our Phase I clinical trial, which will commence in Q4 2022.”

The first set of pre-clinical studies of Avacc 10®, published in Frontiers of Immunology in December 2021, demonstrated high levels of spike-binding immunoglobulin G (IgG) and A (IgA) antibodies in serum,  and the nose and lungs after two intranasal vaccinations 3 weeks apart. Avacc 10® vaccinated hamsters challenged with SARS-CoV-2 were protected from weight loss and viral replication in the lungs and histopathology showed no lesions in lungs 7 days after challenge.

Additional pre-clinical and toxicology study

The objectives of the additional pre-clinical and toxicology study of Avacc 10® were to study the dosing, cross neutralization and safety of the intranasal vaccine. For the dosing study, mice were vaccinated intranasally with two doses of various concentrations of OMV and Spike protein. Three weeks after the last vaccination neutralizing antibodies against the SARS-CoV-2 Wuhan strain and variants of concern Delta, Gamma and Omicron were determined in the sera. High virus neutralizing antibody titers were detected against all the variant viruses. Syrian hamsters were used to study viral replication after challenge with SARS-CoV-2. A reduced viral load in throat and lungs and highly reduced lung lesions were observed in Avacc 10® vaccinated animals exposed to placebo vaccinated, challenged animals. Furthermore, delayed transmission of Avacc 10® vaccinated, challenged animals to placebo vaccinated animals was observed.

Repeated toxicity study

The purpose of the repeated dose toxicity study was to assess the safety and tolerability of Avacc 10® when administered through the intranasal route in New Zealand White Rabbits. Animals were vaccinated 3 times with  Avacc 10® , and control animals with OMV only, or saline buffer. Toxicity was monitored until 2 weeks after the final vaccination. No clinical signs of toxicity nor morbidity/mortality were found in any of the groups, and no gross pathological changes were observed, demonstrating the safety of OMV based vaccine. All Avacc 10® vaccinated animals showed high IgG antibodies levels against Spike as well as virus neutralizing antibodies.Based on the outcome of the Phase I trial, Intravacc will seek manufacturing and commercialization license partners.

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Bilthoven, the Netherlands / Munich, Germany, 6 July 2022 – Intravacc, a world leading contract development and manufacturing organization (CDMO) of preventive and therapeutic vaccines and the German Center for Neurogenerative Diseases (DZNE), have been awarded a funding of € 2.5 million from the European Union (EIC Transition Grant) to further develop a prototype ALS vaccine, including process development, scale-up and toxicology study. The project aims to develop the vaccine candidate identified at DZNE to the point where it can be clinically tested in humans.

ALS is a fatal neurodegenerative disease that is triggered by protein aggregation in the brain and spinal cord motor neurons that leads to paralysis and ultimately to death. Gene mutations have been identified as triggers for some forms of the disease. About 5-10% of all ALS cases are caused by a mutation in the C9orf72 gene, making it the most common genetic ALS variant. In contrast to most individuals, these patients carry a massively expanded repeat region in an otherwise silent part of this gene. Nevertheless, the research group of Prof. Dr. Dieter Edbauer at DZNE, discovered that these extra sequences are translated into toxic proteins, most abundantly, large chain-like molecules called poly-Glycine-Alanine (poly-GA). These molecules trigger downstream pathology in mouse models, ultimately causing neurons to die.

An Experimental Vaccine

DZNE developed an experimental vaccine that instructs the immune system to produce antibodies against these harmful poly-GA molecules. In a mouse model, this reduces poly-GA aggregates and largely prevents motor deficits. Regular vaccination is required to maintain sufficient antibody levels. In humans, over 2,500 prevalent C9orf72 ALS cases have been reported in the US, and Europe alone. An estimated 9,000 mutation carriers who currently show no symptoms but are at risk to develop disease within 10 years could also benefit from this approach. Similar vaccine concepts could perhaps even help patients that develop a related disease, called frontotemporal dementia.

Prof. Dr. Dieter Edbauer, group leader at DZNE, said:
“Before we can test this approach in ALS patients, we need to establish clinical grade production of our vaccine and do further safety studies. We are grateful that the EU supports this development with the EIC Transition Grant. All in all, we hope that with the help of Intravacc, results from this joint project will advance the broad application of vaccines in debilitating neurodegenerative diseases.”

Dr. Jan Groen, Intravacc’s CEO, said:
“There is an unmet need for effective, disease-modifying therapies to treat ALS patients. The goal of our current project is to develop the vaccine to the point where it can be tested in humans. Clinical trials for C9orf72 ALS, which is the most common genetic variant of ALS, are expected to commence in 2025. Our experience in developing similar conjugate vaccines for infectious diseases will greatly accelerate the preclinical development and support the start of the first ever in human ALS vaccine clinical trial.”

About ALS

Amyotrophic Lateral Sclerosis (ALS), the most frequent motor neuron disease, is a progressive neurodegenerative disease of motor neurons in the brain and spinal cord, resulting in progressive paralysis, with death typically within 2 to 5 years of diagnosis. ALS typically occurs in people between 40-70 years old, with men affected slightly more often than women. To date, there is no cure for ALS. Current therapies can only alleviate symptoms, but cannot stop neuron loss and progression of the disease. ALS is a rare disease with multifactorial etiology, and the precise pathogenic mechanism is still unknown. In most of patients (85-90%), the cause of ALS is unknown. This situation is referred to as “sporadic ALS”. 10-15% of ALS cases have genetic causes. Genetic variants of ALS triggered by known mutations, such as the C9orf72 repeat expansion offer a unique chance for targeted therapy.

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Bilthoven, the Netherlands, 5 July 2022 – Intravacc B.V., a world leader in translational research and development of preventive and therapeutic vaccines, today announced the publication of the 2021 annual report and the expansion of its management team, with the appointment of Dr Maj-Britt Kaltoft as Chief Business Officer, and Dr Edwin Kets as Director Vaccine Process Development. In addition, Intravacc’s Chief Financial Officer Nathalie Laarakker has been appointed to the board of directors.

The annual report for the financial year 2021, including a review of figure, performance and Financial Statements for the Year ended 31 December 2021, is available online and can also be downloaded as PDF. A summary of Intravacc’s financials are also published in the Annual Report Management of State Participations 2021 (page 165-168, in Dutch).

Furthermore, Intravacc B.V. is very pleased with the expansion of its management team and board of directors. Each of these respective roles will support Intravacc’s hybrid business model and the continued advancement of the company’s vaccine contract development portfolio of candidate vaccines

Dr. Jan Groen, Intravacc’s CEO, said:
“As we are building our professional contract development and vaccine manufacturing organisation, we need  an experienced and robust executive team that knows how to get things done. We are very pleased to strengthen our team with these key appointments and I am excited about the expertise and new ideas they have to offer Intravacc.”

Maj-Britt Kaltoft PhD, Chief Business Officer, is a senior business executive with over 25 years of experience in out-licensing, contracting, commercialization partnering in the life science industry. Prior to joining Intravacc, she held several senior international managerial positions in BD, with Nova Nordisk, Nycomed, H. Lundbeck, and the Danish State Serum Institute. Dr. Kaltoft holds a PhD degree in molecular biology and protein biochemistry from the University of Copenhagen, Denmark and a master’s degree in international business from Seattle University in Washington, USA.

Edwin Kets PhD, Director Vaccine Process Development has worked in the veterinary vaccine industry at Merck Sharpe and Dome (MSD) in several managerial positions for nearly 20 years. In his last role he was executive director of global animal health manufacturing science & technology EU. He also held managerial positions at Organon and the University of Wageningen. He holds a MSc in biology  from the University of Utrecht and a Master’s degree in biology from the Radboud University in Nijmegen and PhD in biotechnology from the Wageningen University.  Mr. Kets’ key responsibility at Intravacc will be to direct and manage all aspects of the process development department, which supports Intravacc’s four proprietary vaccine platforms.

Nathalie Laarakker RA, joined Intravacc as Chief Financial Officer on April 1st 2021. On January 1st 2022,  she became a member of  the Board of Directors as an executive director. Intravacc’s board now consists of two members, with Intravacc’s CEO Dr. Jan Groen acting as chairman.

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Bilthoven, the Netherlands, 2 May 2022 – Intravacc B.V., a world leader in translational research and development of preventive and therapeutic vaccines, today announced the signing of an exclusive licensing agreement with Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd (“Zhifei Lvzhu”) in China for Avacc 3, an OMV-based whooping cough vaccine.

Under the terms of this agreement Zhifei Lvzhu will receive an exclusive license for the Chinese territory and non-exclusive for Africa, South America and selected Asian countries. Under the agreement Intravacc will receive milestone and upfront payments and royalties over net sales. Both parties will continue to collaborate to tailor the Avacc 3 concept vaccine for the respective territories, including upscaling, toxicology and clinical trials.

Avacc 3 induces strong systemic response

Current vaccines against whooping cough have disadvantages. Inactivated whole cell vaccines are relatively reactogenic, resulting in reduced use in vaccination programs. Subunit vaccines, on the other hand, have limited efficacy. This results in outbreaks of whooping cough, even in vaccinated populations. Asymptomatic carriage facilitates spreading of the bacteria and a vaccine that prevents this, could contribute to herd protection. Intravacc’s Avacc 3, a homologous Bordetella pertussis candidate vaccine based on Intravacc’s OMV platform, induces a strong systemic immune response. When administrated intranasally, it induces both a strong systemic and a strong mucosal immune response.

Dr. Jan Groen, Intravacc’s CEO, said:
“We are very pleased to partner with Zhifei helping to improve the prevention of whooping cough in China. This is Intravacc’s second OMV-based licensing agreement with a pharmaceutical company, thereby expanding the global reach of our proprietary OMV platform technology.”

Bordetella pertussis

Whooping cough, or pertussis, is a highly contagious respiratory disease that is caused by the Gram-negative bacterium Bordetella pertussis and transmitted through Flügges droplets. It is a strictly human pathogen and all age groups can be infected. However, infants are the main risk group. Worldwide, there are an estimated 24 million cases of pertussis and about 160,000 deaths per year. Diagnosis of pertussis is often difficult in the early stage with only a mild cough, and fever is uncommon. Later, the severity of the disease increases with pneumonia, vomiting and increased coughing, which in infants can lead to death.

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Bilthoven, the Netherlands, and Paris, France, 22 March 2022 – Intravacc, a world leader in translational research and development of preventive and therapeutic vaccines, today announced the publication of a GMP (Good Manufacturing Practices) manufacturing and formulation process for a monovalent semi-synthetic conjugate vaccine candidate against Shigella flexneri 2a (SF2a). This candidate vaccine was developed at the Institut Pasteur (Paris, France)and the GMP process is described in the peer reviewed scientific journal ACS Central Science of the American Chemical Society,  in a paper entitled “The first-in-human synthetic glycan-based conjugate vaccine candidate against Shigella”.

GMP synthesis of conjugate vaccines

SF2a is a species of enteric bacteria that causes disease in humans. The disease caused by the ingestion of the Shigella bacteria is referred to as shigellosis, which is associated with diarrhea.
This publication discloses the yet unreported feasibility of the GMP synthesis of conjugate vaccines featuring a unique homogenous synthetic glycan hapten fine-tuned to protect against an infectious disease. The scale-up feasibility of the bioconjugation step under GMP conditions resulted in a high yielding process, and a reproducible and controllable SF2a vaccine production process. Preclinical and clinical batches for polysaccharide conjugate vaccines and (non-)compendial tests, complying with ICH guidelines and WHO recommendations, were produced. The obtained synthetic glycan-based conjugate vaccine passed all toxicity-related criteria, was immunogenic in rabbits and elicited bactericidal antibodies against SF2a in mice. The induced IgG serum antibodies recognized a large panel of SF2a circulating strains.

First -in-human trial demonstrated safety and immunogenicity

The results of the first-in-human trial for the SF2a semi-synthetic glycan-based conjugate vaccine candidate developed at the Institut Pasteur demonstrated safety and immunogenicity. Achievements of the development of this candidate SF2a vaccine are part of Stopenterics, a European consortium which has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013).

Phase IIa trial ongoing

An age descending phase IIa trial to investigate the safety and immunogenicity of this SF2a vaccine candidate in the infant target population in endemic countries was initiated in 2020 (clinicaltrials.gov NCT04602975). The estimated completion date is expected in Q3 2023.

Dr. Jan Groen, Intravacc’s CEO, said:
“This is Intravacc’s second successful development of a GMP manufacturing process for a conjugate vaccine based on Tetanus. Our first conjugate vaccine for Haemophilus influenza type b (Hib) was transferred to international partners worldwide and has been on the market for several years now.”

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Bilthoven, the Netherlands, 5 January 2022 – Intravacc, a global leader in translational research and development of therapeutic vaccines and vaccines against infectious diseases, today announced a partnership with Dutch Leiden University Medical Center (LUMC) to develop and evaluate a new nasal spray corona vaccine in a clinical phase I/II study. This new vaccine, NANOVAC, is based on microscopic soluble nano-spheres, containing synthetic mini proteins that, when administered as a nasal spray, directly protects the upper respiratory tract including nasal passages and throat (mucosa) before the virus reaches the lungs. The design of this type of vaccine thereby makes the vaccine broadly protective, harnessing both arms of the immune system, against SARS-2 (COVID19) but also SARS-1, MERS, and other beta coronaviruses. Intravacc also develops AVACC-10, a nasal spray corona vaccine based on Outer Membrane Vesicles. Nasal spray vaccines are ideal to prevent and stop transmission to other people and are a perfect solution for people with a fear of needles.

Trials supported by Health~Holland

The planned clinical phase I/II study is made possible in part by the Top Consortium for Knowledge and Innovation (TKI) of Health~Holland, part of the Dutch top sector Life Sciences & Health. Health~Holland plays a connecting role between the business community, government, research institutes, patients and social organizations.

Positive results from preclinical studies

Dr. Luis Cruz’s team, responsible for LUMC’s Translational Nanobiomaterials and Imaging department, spent more than a year working on the new, sustainable and simple nasal spray vaccine. The preclinical studies in animals showed surprisingly positive results. The phase I/II clinical study is led by Dr Leo Visser of the Infectious Diseases Department of the LUMC. Intravacc will focus on a number of additional and preliminary preclinical exercises and the process development research of the vaccine through a scalable vaccine production process using its expertise in GMP vaccine production. The nasal spray vaccine will be tested on healthy volunteers to evaluate safety and tolerability. This phase I/II clinical trial is expected to start at the end of 2022 and the first study data is expected in the first half of 2023.

Dr. Luis J. Cruz, head of LUMC’s Translational Nanobiomaterials and Imaging department, said:
”Intravacc and LUMC create major synergy by combining distinct complimentary expertises and competencies. A promising collaboration!”

Mode of action

NANOVAC is intended to protect humans against current and future COVID-19 variants. The nano vaccine candidate is not only based on spike protein but also other target proteins in the coronavirus. It consists of a nanoparticle formulation containing multi-epitopes polypeptides of the immunogenic spike (S) protein of SARS-CoV-2 (COVID19), as well as other 100% conserved epitopes derived from distinct coronavirus proteins of which important targeting has already been identified for inducing a complete humoral systemic and mucosal immune response, and cellular immunity response, both neutralizing antibodies and T cells, both for immediate immunization, and for a longer-term defense.
To enhance the effectiveness, the adjuvant hepatitis B core antigen HBcAg is used, which already has a proven effect in a nasal spray vaccine against liver inflammation. The HBcAG particle has been safely administered intranasally, serving as a carrier for nasal route and an immunostimulant for the mucosal immune cells of the nasal passages and upper respiratory tract. The vaccine does not apply the more recently used mRNA technique or inactivated cold viruses (vectors).

The other COVID nasal spray vaccine that Intravacc is working on, AVACC-10, uses OMVs, vesicles that bacteria communicate with and that serve as a platform to transport a protein that can (eventually) fight COVID.

Platform-technology for NANOVAC and AVACC 10

In addition to COVID-19, the platform technologies on which these vaccines are based can also be used for the development of vaccines against a variety of other diseases. Several clinical studies with vaccine candidates developed on these platforms and administered by nasal spray or injection, have demonstrated safety for use in humans. NANOVAC and AVACC 10 can be quickly adapted to new COVID virus variants and then produced rapidly in large quantities and cheaper than existing vaccines. In addition, they can be stored at room temperature, which simplifies transport over longer distances. This makes these vaccines an ideal solution for lower-income countries with a more limited medical infrastructure.

Jan Groen PhD, Intravacc’s Chief Executive Officer comments:
“I am particularly pleased with Intravacc’s input in the development of this new nasal spray vaccine. This concept and Intravacc’s own AVACC-10 vaccine are potential game-changers in the fight against COVID. According to renowned immunologist Professor Ed Lavelle, of Trinity College Dublin, transmission of the virus is best blocked where it enters the body. It is therefore preferable to administer the vaccine via a spray in the nose for direct immunization of the throat and nasal mucosa (2022 nasal spray interview).” 

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