100 Days Mission to respond to a future Pandemic

Recent scientific publications show that vaccines delivered to the lungs are more effective than traditional injectable vaccines and provide broader cross-reactive and longer-lasting protection.

Revax patented low-dose technology enables the world to be better prepared and can meet the G7/WHO challenge to deliver new vaccines to meet existing or emerging respiratory pandemic threats in 100 days or less. Our technology delivers the following benefits.

The G7 Pandemic Preparedness Partnership recently published their roadmap to ensure that diagnostics, therapeutics and vaccines are available within the first 100 days of a pandemic: The roadmap can be found here.

Revax Biotech is an innovative vaccine company with a novel, patented technology to deliver ultra-low doses of vaccine to the human respiratory tract and lungs rather than via injection. This paper sets out how Revax Biotech aims to enable this mission to be able to respond to the next pandemic within 100 days.

Pandemics are not new, indeed a peer-reviewed paper published in 2008 (Jones et al., 2008; Nature, 451, 990-993) analysed the incidence of emerging infectious diseases by literature searching that occurred between 1940 and 2004. In short, 334 newly emerged diseases were reported in that time, some 60% of which are zoonotic in origin. The criterion for inclusion was the actual incidence of disease and not just emergence of the pathogen. Interestingly, 54% of these emergent diseases were either bacterial or Rickettsial in origin which is somewhat contrary to the perceived view that viruses and in particular RNA viruses are the most likely pathogens to cause disease. This view is premised on the basis of their higher rates of mutation due to poor error-correction and high rates of nucleotide substitution. However, the ongoing pandemic caused by SARS-CoV-2 demonstrates that RNA viruses certainly have the ability to cause global pandemics and respiratory pathogens in general are more easily transmitted within and between populations, of course.

To address the title of this paper, how do we reduce the time to produce a vaccine against a newly emergent pathogen? To create a timeline of vaccine discovery, development, manufacture and evaluation some critical assumptions have to be made. Firstly, we have made the assumption that the initial period within the 100 days is entirely taken-up by characterisation of the pathogen, genomic sequencing and establishing the criteria for laboratory and larger scale culture. To this end we have assumed that 20% (20 days) of the 100 days is consumed by this process. This has basis in science from previous outbreak & pandemic respiratory pathogens.

For example, on March 12th 2003 the WHO issued a global alert for a severe form of pneumonia of unknown origin and on April 14th, CDC published the genomic sequence of the SARS virus, believed to be responsible (but not yet proven according to Koch’s postulates) for the outbreak. This was a total of 33 days during which the conditions for virus culture and isolation had been established and some limited animal infection studies conducted. Now 18 years later, genomic sequencing is much faster with such a viral pathogen being completely genomic sequenced in 24 to 48 hours without the need for isolation and culture.

Similarly, the timeline of the nvH1N1 influenza pandemic in 2009 supports the view that 20 days for characterisation and culture is not an unreasonable assumption. The WHO issued a global alert on April 25th 2009 but did not declare a pandemic (community transmission of disease in all 6 WHO global regions) until June 11th. This pandemic was slightly unusual since it was caused by influenza which is a well-characterised virus, however, taking the response in the UK as an example, the first infections here were reported on May 1st 2009 and these viruses were fully sequenced and published on Genbank on May 18th 2009.

  1. Revax Biotech Technology Advantage 1: There now remain 80 days in which to develop and manufacture a vaccine and this is the approach that Revax will employ. Firstly, it is important to acknowledge that there are number of key features of the Revax patented technology which make our approach intrinsically well-adapted to the development and manufacture of vaccines in a short timescale. The first key point is that the vaccine is comprised of whole bacteria or virus, grown in culture and inactivated, in much the same way that seasonal influenza vaccines are currently made. The advantages of using whole, inactivated pathogen as the immunogen in a vaccine are two-fold. Firstly, no decisions have to be made regarding the major antigenic epitopes and/or genes in the pathogen. Although this is relatively straightforward for viruses, it is much more complex for bacterial pathogens and so using whole, inactivated material removes the need to determine which is the optimal, immunodominant antigen as they are all used. Secondly, the use of multiple antigens has been demonstrated many times to provide effective protection; there remain many whole-virus or acellular vaccines in use and these all have high efficacy (examples include influenza, pertussis and polio vaccines, all of which have a long history of safe and effective use). Our own studies have shown that delivery of whole-virus, inactivated vaccines to the respiratory tract and lungs induces a powerful immune response at very much lower doses than are required for injectable vaccines and in the correct place to allow the body to fight respiratory infection. A current example of the power of inactivated whole-virus vaccines is a recent, peer-reviewed publication in The Lancet (Lancet 2021; 398: 213–22) which reports on the safety and efficacy of a whole-virion, inactivated SARS-CoV-2 vaccine (CoronaVac) manufactured by Sinovac. Given that we are using whole pathogen material, this stage does not require any time allocation as we move straight into laboratory and then manufacture scale culture.
  2. Revax Biotech Technology Advantage 2: Key point two then is that our pre-clinical studies have shown that our technology is effective at just 1/200,000 of the usual dose for injection. Let’s make another assumption that we need as much as 1/100,000 of the usual injectable dose, so more than our own studies have already proven but far less than “conventional” vaccines. As a worked example of the effect of an ultra-low dose vaccination regimen, for the current SARS-CoV-2 pandemic, to vaccinate the UK alone requires 13.6 million litres of virus culture to make the Oxford-Astra Zeneca vaccine doses; the Revax technology approach would require only 136 litres of culture. Thus, the second reason that Revax technology meets the challenge to develop and manufacture vaccines within 100 days is that very much smaller volumes of vaccine are required, which, of course, results in ease and speed of manufacture. The European Commission funded a project between 2008 – 2013 called FastVac. The aims of this programme of work were to enhance preparedness against the next pandemic by looking at ways to improve rational vaccine design and manufacture. One of the output work-packages from this programme looked specifically at using Process Analytical technology (PAT) approaches to speed up manufacture. PAT uses mechanisms to design, analyse, and control pharmaceutical manufacturing processes through the measurement of critical process parameters (CPP) which affect critical quality attributes (CQA). Such an approach using PAT principles can be used for rapid vaccine manufacture. Given that the Revax technology uses such a low dose of vaccine, we estimate that vaccine material could be easily be ready for pre-clinical trials to start 30 days after the pathogen characterisation work is complete. This now gives a total of 50 days of the 100 used and we are ready to start immunising animals in pre-clinical studies. Pre-clinical studies are likely to take another 30 days from the 100, making 80 and leaving 20 days remaining. These remaining 20 days will be used to complete testing and package material ready for nebulisation and delivery to patients, well within the 100 days target.
  3. Revax Biotech Technology Advantage 3: The third key point, an approach which again contributes to the rapid development, manufacture and dissemination of vaccines in a pandemic situation, is the Revax technology delivery method. Our vaccines are delivered as an aerosol generated using a conventional, medical-grade nebuliser system or asthma-inhaler type approach. This again endows the technology with two main benefits; firstly it overcomes the need for needles and staff trained to deliver vaccinations as with minimal training, the patients themselves can deliver their own vaccine dose in the same way that asthma patients deliver their own medication via a simple nebuliser device and multiple dose canister. Exactly the same approach can be used for vaccine delivery, with a multi-dose cannister used to vaccinate potentially tens if not hundreds of patients. Delivery of vaccines to the respiratory system is gaining significant interest, as it is particularly effective for respiratory infections, unsurprisingly! A recent example is the delivery of a SARS-CoV-2 vaccine to the respiratory tract and lungs which may be found in the peer-reviewed publication “Combating COVID-19: MVA Vector Vaccines Applied to the Respiratory Tract as Promising Approach Toward Protective Immunity in the Lung” (published in Frontiers in Immunology, doi: 10.3389/fimmu.2020.01959).
    The second advantage is that this system overcomes needle-phobia which affects over 70 million people worldwide and is a major barrier to population-level vaccination campaigns. Another useful side-benefit of this technology is stability. Because inactivated materials are inherently more stable than other vaccine preparations, they can also be freeze-dried, further enhancing stability, shelf-life and removing the requirement for cold-chain storage and transport.

SUMMARY:
To summarise, the patented Revax Biotech technology offers the ability to develop, manufacture and start to disseminate vaccines against a hitherto unknown pathogen well within the 100 days of this challenge. The benefits of this technology approach are as follows:

  1. Uses inactivated, whole pathogen material as the immunogen – no decisions regarding antigenic proteins or genes needs to be made thus speeding up this first phase of the process.
  2. Uses an ultra-low dose at between 1/100,000th and 1/200,000th of the dose of conventional vaccines thus speeding up manufacture as much smaller volumes of material are needed.
  3. Uses an inhalational delivery system which has been shown to be much more effective for respiratory pathogens and overcomes need for trained staff for injections, needle-phobia and cold-chain issues. Another major advantage of this method and route of delivery is the induction of an immune response in the right place to fight infection.
  4. Revax technology clearly allows the rational design, manufacture and testing of vaccines in a pre-clinical animal model, all completed within 80 days of a pandemic being declared. These timelines could, no doubt, be further shortened to provide vaccines even faster.

By bringing together key players in aerosol delivery, academic excellence in vaccines, industrial support and clinical research organisation expertise, Revax Biotech promises to deliver a revolution in vaccination. This will enable rapid development of safer vaccines at dose levels which will be economic for global distribution due to the low volume of material and no cold chain requirement and therefore provide for the Inclusion of LMIC and developing countries.

What is needed to make this happen.