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European Biopharmaceutical Review

Heal the World

Previously, infectious diseases were the leading cause of death. In 1900, pertussis, diphtheria and scarlet fever were together responsible for an annual death toll of 65,000 children in Germany. Nowadays, such deaths are the rare exception rather than the rule. Vaccinations have been a major factor in this positive change, along with improved socioeconomic conditions and increasing availability of antibiotics.

According to the WHO, immunisations are among the most effi cacious and cost-effective approaches to combat and control infectious diseases. With regard to their direct impact on public health, they are second only to ensuring a clean supply of drinking water. In addition to protecting the individual against pathogens transmitted from person to person, many vaccinations have an additional effect: collective protection of the population. This prevents the occurrence of epidemics and safeguards those who cannot be vaccinated for medical reasons. At high vaccination rates, infection chains may be interrupted and pathogens eliminated regionally, eventually leading to eradication worldwide.

Nonetheless, a global immunisation strategy still faces many obstacles, including:

Anti-Vaccination Movement
Vaccination is, and always has been, associated with certain risks, although the incidence of serious adverse events remains low. For example, the oral polio vaccine – developed in the 1990s – saw one adverse reaction for every 2.4 million doses, before an even safer product was introduced shortly before the millennium. In Germany, it is estimated that between 4-5% of the population are radical opponents of vaccination and do not vaccinate their children against any disease. But the graver problem lies with the 20-30% who make the personal decision to avoid being vaccinated. This remains a concern because, in order to prevent the spread of infectious diseases, there is a need to vaccinate the majority of the population.

Lack of Innovation
For more than a century, vaccines have been developed according to the principles of Pasteur – isolation, inactivation and injection of the infectious agent of a communicable disease. All currently available vaccines are based on killed or attenuated microorganisms, or purifi ed subunits thereof, such as toxins detoxifi ed by chemical treatment or purifi ed antigens, like proteins or conjugated polysaccharides. Vaccines manufactured in accordance with Pasteur’s principles allow for the control and, in some cases, eradication of many important infectious diseases.

However, despite these achievements, this strategy is reaching its limits; not only is it tedious, but it remains limited against a lack of immune-dominant and suffi ciently protective antigens, as well as in non-culturable microorganisms. Only state-ofthe- art immunology and molecular biology hold promise for developing vaccines against these pathogens.

Lack of Global Immunisation
Newer, more expensive modern vaccines protect against diseases that occur predominantly in poorer countries, like pneumococcus and rotavirus. According to the WHO, pharmaceutical companies used to offer their medications at lower prices to developing countries, while simultaneously charging higher amounts in industrialised nations. Unfortunately, this is no longer lucrative for many fi rms, so vaccines have either become expensive or, alternatively, are not provided at all. For example, severe pneumococcal pneumonia still claims the lives of more than 700,000 children in poorer countries because readily developed vaccines do not reach the market (1).

Cold Chain Requirements
Product stability is the most important factor for successful vaccine development. Thousands of deaths due to infectious diseases could be prevented annually if temperature-sensitive medications were stored properly during shipment (2). The stability of drugs – especially vaccines – is a big problem in tropical and developing countries because the life-saving active compounds are often inactive before they reach the population.

The delivery of vaccines from the manufacturer to the patient can take up to 18 months and most vaccines must be kept cool this entire time. The WHO estimates that half of supplied vaccines have to be discarded as the cold chain requirements are not met during transportation. As a result, the manufacturing of new drugs should focus on improved stability at extreme temperatures to ensure optimal efficacy, in spite of diverse storage conditions. Governmental and non-governmental organisations – such as the WHO, EU, the Bill & Melinda Gates Foundation and PATH – specifically promote innovation in this area.

High Prices
Vaccines are still too expensive to ensure global immunisation of the world’s population. Much of the $7.5 billion raised for Gavi, the vaccine alliance, is used to pay for vaccines (3). For this reason, Pfizer declared its readiness to support Gavi with further price reductions of its pneumococcal conjugate vaccine, Prevenar 13, until 2025. The projected saving per dose is $0.20. Médicins Sans Frontiéres Germany has criticised Pfizer, believing that a discount from $3.30 to $3.10 per dose was simply not enough. They called for a signifi cant price reduction so the vaccine would be affordable to all countries and aid agencies. In addition, there are demands for greater transparency across the vaccine market, especially in terms of production costs and trade margins (4).

mRNA Development


The advantages of nucleic acid-based vaccines are obvious. They are quick and inexpensive to produce, and all the sequences of antigens can be encoded on them. The option of using nucleic acids was fi rst investigated in the early 1990s, but the focus of development at that time was on DNA vaccines, primarily because of the perceived stability of DNA. RNA – as a nucleic acid – was believed to be instable, resulting in doubts about its general use and storability.

The development of DNA vaccines was, in comparison, less successful compared to the current RNA-based vaccines (5). After the death of Jesse Gelsinger, a participant in a gene therapy study, almost all DNA-based developments were halted in early 2000. Around the same time, the potential of using mRNA as a vaccine was first demonstrated by Hoerr et al (6). Scientists injected mRNA directly into the skin of mice and, quite unexpectedly, the mRNA was found to be robust enough to be taken up by cells and express the antigen. What is more, the gene product was not only expressed, but also elicited a specific T cell response. Interestingly, the research group experimented not only with mRNA consisting of naturally occurring nucleotides, but also with mRNA that was synthesised from chemically-modified building blocks.

Surprisingly, the superiority of the chemically-modified building blocks could not be established in these experiments, so the focus of all further research activity was exclusively on the naturally occurring RNA. It was found that optimisation of the antigen expression and simultaneous efficient immune stimulation could be achieved with a special formulation of the mRNA, the so-called RNActive® technology (7). These optimised RNActive vaccines allow for direct intradermal or intramuscular administration, and elicit cellular and humoral immune responses without further adjuvants.

Success Stories

In Nature Biotechnology, Petsch et al presented results revealing effective protection by a prophylactic RNActive flu vaccine (8). The administered mRNA proved to be immunogenic, and induced a balanced, sustainable and protective response against influenza A virus infection in various animal species. This vaccination strategy was successfully applied both in newborn and older mice, as well as in larger animals such as pigs.

In the course of their development, RNActive vaccines have been tested in more than 300 patients across several clinical trials, displaying a favourable safety profile (9). The RNA, as a carrier of RNActive technology, is a natural messenger and is completely degraded after a few days, making multiple injections over time possible. The molecules are also stable enough to efficiently deliver all the required information to the immune system with any shot of vaccination.

In 2014, the EU awarded a prize of €2 million for the successful development of innovative technologies that enable vaccines to remain independent of a cold chain during their transportation and storage. mRNA products manufactured using the RNActive technology proved to be stable and active for several months at temperatures of 40°C, making them ideal to facilitate the provision of innovative vaccines to developing countries. At the same time, their manufacturing costs are relatively low, as it is a matter of scalable and synthetic nucleic acid synthesis, and diverse vaccines can be produced in the same production unit. Furthermore, very fast production is likely; in one case study, in a hypothetical pandemic scenario, it was possible to manufacture a vaccine according to Good Manufacturing Practice standards from scratch within 6.5 weeks.

Positive Prospects

mRNA is the basis of a classic platform technology which makes it possible to express a wide variety of antigens; this has so far been shown in several clinical trials. Its potential has been widely recognised with the aim to jointly develop mRNAbased vaccines for developing countries, as well as innovative vaccines for industrialised nations. Initial projects have been launched with rotavirus, HIV and respiratory syncytial virus and, if efficacy is demonstrated in further trials, it will surely only be a matter of time before old prophylactic vaccines are finally withdrawn and replaced by innovative mRNA alternatives.

References

1. Tocheva AS et al, Declining serotype coverage of new pneumococal conjugate vaccines relating to the carriage of Streptococcus pneumoniae in young children, Vaccine 10 29(26): pp4,400-4,404, 2011
2. WHO, Temperature sensitivity of vaccines, 2006. Visit: www.who. int/vaccines-documents
3. Visit: www.msfaccess.org/content/right-shot-bringing-downbarriers-affordable-and-adapted-vaccines
4. Visit: www.aerzteblatt.de/nachrichten/61604/mehr-als-7-5-milliarden-us-dollar-fuer-gavi-impfallianz-kritikerimpfstoffe-zu-teuer
5. Ulmer JB, Mason PW, Geall A and Mandl CW, RNA-based vaccines, Vaccine 30: pp4,414-4,418, 2013
6. Hoerr I et al, In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies, Eur J Immunol 30: pp1-7, 2000
7. Fotin-Mleczek M et al, Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity, J Immunother 34: pp1-15, 2011
8. Petsch B, Schnee M and Vogel AB, Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection, Nat Biotechnol 30: pp1,210-1,216, 2012
9. Kübler H et al, Self adjuvanted mRNA vaccination in advanced prostate cancer patients: A first-in-man Phase 1/2a study, Journal of Immuno. of Cancer 3(26), 2015

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Ingmar Hoerr is Chief Executive Officer of CureVac. He founded the company in 2000, together with Florian von der Mülbe and other colleagues, to target R&D of mRNA-based drugs. Today, the firm’s current research is focused on the development of cancer immunotherapies and prophylactic vaccines. Ingmar received his PhD from the University of Tübingen, Germany, and his MBA from Danube University, Austria.
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