The stuff of dreams: The vaccine to protect against SARS-CoV-2 infection.

The question of when a vaccine to protect against SARS-CoV-2 infection might be available is not a simple one. This article is about why vaccines are needed, how they are developed and when a first vaccine against SARS-CoV-2 infection might be available.

IMPACTS.

Vaccinations have been reliably reducing disease burden and mortality in the population for many decades. With the development of vaccines and their widespread use, it has been possible to significantly reduce cases of a large number of bacterial and viral infectious diseases worldwide.^[1] (e.g. tetanus, diphtheria, measles, mumps, rubella, poliomyelitis).
Smallpox, caused by the smallpox virus, serves as a prime example of successful mass vaccination when the WHO proclaimed the eradication (eradication) of smallpox in 1979^[2]. Vaccinations develop their protective effect by building up a so-called acquired, specific immunity, among other things through the formation of so-called antibodies, which are specifically directed against the pathogen or its products.(Note: the effective elimination ("eradication") of viruses in the human population by means of vaccines is only possible if humans are the only hosts of the virus, i.e. the virus cannot be found in the animal kingdom, because a transfer of the virus from the animal kingdom to humans cannot be ruled out, as we have just experienced (again)).

IMMUNITY.

The use of specific vaccines is intended to achieve so-called "herd immunity". This is understood to mean a broad immunity situation in the population. Vaccine-immune individuals are no longer infectious and no longer carry the virus. The chain of infection is interrupted and thus contributes to the elimination of the virus circulating in the population.
A viral infection is always a host-virus interaction. A race over time after initial contact with the virus ("exposure"/infection) and its viral replication in the host. The immune system of the host/human reacts to a virus exposure immediately with a so-called innate immunity and then the over a period of a few days (approx. >10 days) with a specific, acquired immunity.

THE SELF-LIMITING INFECTION.
Self-limiting infection is a form of viral infection in humans which, after the infection has been passed, both eliminates the virus (the human no longer serves as a virus carrier and is therefore no longer infectious) and leaves an immunity, which in the least case is a virus-type-specific immunity.

Notice.
In principle, there are therefore two ways to become immune to an acute virus; once through vaccination (if available) and once through a passed infection (as also seems to be the case after a passed SARS-CoV-2 infection (as of 30.03.2020)).

VIRUS STRATEGY.

Viruses have "strategies" to reproduce successfully. For example, the SARS-CoV-2 coronavirus (which I consider to be an acute virus) obviously "pursues" a strategy to infect as many people as possible and thus ensure progeny.^[3]) obviously pursues the strategy of infecting as many people as possible in order to secure offspring(Note: Viruses have no pleasure in sexually reproducing). Viruses are denied the pleasure of reproducing sexually, which otherwise ensures offspring in the animal kingdom). Since acute viruses need a host to reproduce, viruses, and I include the coronavirus among them, do not normally "strive" to kill humans after infection. If the host is dead, there will be no more offspring.

THE PANDEMIC SARS-CoV-2.

However, the pandemic coronavirus (SARS-CoV-2), unlike the seasonal, circulating coronaviruses, has developed new properties or characteristics that appear to be associated with increased virulence (the potential of the virus to make people sick).(Note that a separate blog post is dedicated to the genetic relationship of SARS-CoV and seasonal viruses of the coronavirus family, to the new SARS-CoV-2, which belongs to the coronavirus family). In about 10-30% of cases, the cause of the common cold is a coronavirus infection (endemic (in our region), seasonal coronaviruses: HCoV 229E, NL63, OC43, and HKU1).^[4].

SPECIES or SPECIES BARRIER.

According to current knowledge, the new coronavirus SARS-CoV-2 belongs to the so-called zoonotic viruses. These are viruses that have been transmitted from animals to humans, such as Nipah, Ebola, HIV, SARS-CoV and MERS-CoV. These viruses usually have their reservoir in the animal kingdom ("are at home there"). Breaking the species barrier of SARS-CoV-2 (from bats via a possible intermediate host to humans), it has acquired new pathogenic (disease-causing) properties for us by crossing into the human population. The virus has thus encountered an immune-naive human population, i.e. humans have never had contact with this virus before and cannot protect themselves from infection even after exposure (after infection). Whether the virus causes no, mild or severe symptoms depends on the general, individual immunity of the infected person.
(Note: No other virologist than Nathan Wolfe has worked intensively on the reasons and the cause of the emergence of zoonotic/pandemic viruses and has dedicated his research and his life to this question. His results and findings are comprehensively laid down in "The Return of the Plagues" (well worth reading!).^[5].

VACCINE DEVELOPMENT - THAT'S HOW LONG IT USUALLY TAKES.

Producing an effective and safe vaccine against a new virus is a lengthy and complex process. On average, it usually takes about ten to twelve years from research to approval.^[6]:*
The development of vaccines can be divided into the following five steps:

1. Screening phase: Vaccine development begins in the laboratory, where "vaccine candidates" undergo various tests to identify promising substances and molecules.
2. Preclinical development: The identified candidates are tested in animal models and also in cell culture (in vitro). Here, initial information on efficacy, immunogenicity and safety is generated.
3. Clinicaldevelopment: Clinical phase 1, phase 2 and phase 3, to test the safety and immunogenicity of the vaccine, to determine the dose, to detect side effects, whether the vaccine protects against natural infection (efficacy), whether there are interactions with other drugs that the doctor administers at the same time. Clinical phase 3 is the most complex and can last 4 to 7 years.
4. Approval: Only if the clinical development of phases 1-3 is successful can the data be submitted for approval to the relevant regulatory authorities. This process takes about 2 years.
5. Constant monitoring: Even after approval, vaccines are subject to regular controls and their safety and effectiveness are continuously monitored in cooperation with the regulatory authorities.

The clinical studies are carried out on healthy volunteers.
ERRATUM: The following text passages 1.-5. do not refer to quotation no. 6, this was presented erroneously and incorrectly. The following text passages 1.-5. are taken from citation: https://arztundkarriere.com/forschung/die-entwicklung-impfstoffen/ accessed 22.03.2020. Sorry, RH 4 SEP 2020!

So we see that standard vaccine development takes an enormous amount of time. Time that we don't have right now.

WHAT ARE THE STRATEGIES FOR VACCINE DEVELOPMENT TO PREVENT COVID 19 DISEASE?

Strategies for SARS-CoV-2 vaccine development are based on detailed knowledge of the SARS-CoV-2-specific genome (genetic material, the totality of genetic information) and its specifically encoded proteins (proteins whose "information" is located in the genetic material of the virus).^[7].

Vaccine development:

Vaccine development, as reported, is a lengthy process, as vaccine efficacy and safety are top priorities. Analyses of the genetic information of SARS-CoV-2 show a genetic relationship to SARS-CoV. This means that the novel coronavirus SARS-CoV-2 also has so-called conserved regions that are related to the SARS-CoV of 2002/03(note that there must be criteria that support the family affiliation of SARS-CoV-2 to the Coronaviridae family). SARS-CoV and SARS-CoV-2 use the same receptor in the human lung. Knowledge of stable target structures on the host cells, i.e. such as the receptor that the virus needs for infection (entry into the host cell) are an essential prerequisite for the development of effective vaccines, since these are then recognised by the activated immune system after vaccination^[8] and can, for example, prevent the virus from entering the host cell.

Classification of vaccines:

Vaccines contain attenuated or inactivated pathogens, toxoids or purified, or individual so-called recombinantly produced "pathogen components". These are presented to the immune system so that it can prepare for an emergency, an infection. Vaccines are administered to healthy individuals.

(Note i.e. this form of vaccines is referred to as "preventive" (protective) vaccines, which are distinguished from therapeutic vaccines. Therapeutic vaccines, which are very complex and very difficult to produce and whose action is more likely to involve immune cells (e.g. T-cells, "cellular immunity") rather than "humoral" immunity, which involves antibodies, are very few available anyway. Preventive vaccines are thus administered to the healthy person, while therapeutic vaccines are applied to the infected person, quasi as an "antiviral drug" to eliminate a persistent (non-acute) virus).

The very high regulatory requirements for the approval of vaccines have led to more and more pharmaceutical companies withdrawing from this business of vaccine development in the past^[9]. These include vaccines based on recombinant genetic engineering, but also novel nucleic acid-based methods.

A review of SARS-CoV-2 vaccine candidates is listed by Chen et al, 2020.^[10]. These include vaccines based on recombinant genetic engineering, but also novel nucleic acid-based methods.

These 3 platforms are:

1. Whole-virus vaccines: adenovirus vector-based vaccines, (RH adds: live-attenuated viruses, not listed, but this platform is also being pursued, e.g. by using the "MVA-backbone" (Modified Vaccinia Virus Ankara-backbone of the smallpox virus vaccine) )
2. Virus subunit vaccines: (RH: supplemented, "dead vaccines"), recombinant proteins, coronavirus RBD (receptor binding domain), spike (S) recombinant trimers, oral recombinant vaccines.
3. Nucleic acid vaccines: DNA and mRNA (messenger RNA) vaccines (from Moderna/NIH*/CEPI**and CureVac/CEPI**)

NIH: National Institutes of Health, USA; ** CEPI: Coalition for Epidemic Preparedness Innovations (a global public-private partnership alliance between governments, the WHO, the EU Commission, research institutions, the vaccine industry and private donors, including the Bill & Melinda Gates Foundation, to build a research network for the research and development of new vaccines; since 2017: https://cepi.net/)

FAST TRACK - EXPEDITED PATHWAY TO VACCINE APPROVAL.

VACCINE DEVELOPMENT TO COMBAT THE EBOLA epidemic in WESTERN AFRICA 2014.

The major Ebola epidemic in West Africa in 2014 triggered international collaborative efforts to rapidly develop a vaccine against Ebola.

Not only regulatory pathways, but also scientific, technical and financial constraints have been evaluated and addressed by the European Medicines Agency (EMA) and other regulatory agencies to ensure rapid approval of Ebola antiviral drugs and Ebola vaccines to address Ebola outbreaks quickly and effectively^[11]. Since March 2016, the EMA has launched the PRIME (PRIORITY MEDICINES) programme to increase support for the development of medicines (including vaccines) that address unmet medical needs. This voluntary programme is based on increased interaction and early dialogue with developers of promising medicines to optimise development plans and accelerate evaluation so that these medicines can reach patients earlier^[12].

On 11.11.2019, the European Commission approved the Ebola vaccine "Ervebo" for Europe (The vaccine Ervebo was developed on the basis of a combination of platform 1 (attenuated VSV, Vesicular Stomatitis Virus) and platform 2 (VSV contains a protein of the Zaire-Ebola virus)). The vaccine was approved under the "PRIME" procedure - an authorisation procedure of the European Medicines Agency (EMA) in which the evaluation process of urgently needed medicines is also accelerated. Quality, safety and efficacy are nevertheless tested with the same care as in a normal approval process.^[13].

CONCLUSION: From the major Ebola virus outbreak in 2014 to the first Ebola vaccine in 2019: 5-6 years .

VACCINE DEVELOPMENT TO COMBAT THE SWINE INFLUENZA (A/H1N1pdm) PANDEMY 2009.

The so-called swine influenza pandemic began in April 2009, and the WHO proclaimed the pandemic in June 2009. This pandemic triggered an unprecedented collaboration between public health authorities and vaccine manufacturers, resulting in the most comprehensive global response ever undertaken (to date). Efforts were coordinated internationally to accelerate vaccine development, distribution and mass vaccination campaigns. The European Union's (EU) fast-track approval procedures, such as the "mock-up procedure" and the "emergency procedure", enabled vaccines to be made available more quickly, while newly developed mandatory post-marketing surveillance conditions improved vaccine safety^[14].

In response to the 2009 A/H1N1pdm pandemic, GSK (Glaxo-Smith-Kline) developed two A/H1N1 vaccines against this pandemic influenza, both of which contained the so-called AS03 adjuvant system: one vaccine manufactured in Dresden, Germany (Pandemrix), and the other in Quebec, Canada (ArepanrixH1N1). Pandemrix was approved for use by the EMA in September 2009 through the fast-track approval process and through the emergency procedure, which are accelerated approvals (about 70 days instead of 210 days), after a pandemic had already been declared. Arepanrix H1N1 was approved in Canada in October 2009 under an interim licensing regulation, the approval of the vaccine based on limited clinical data paired with imposed obligations, following licensing^[15].

WHAT QUANTITIES OF VACCINE WERE NEEDED? - BILLIONS OF DOSES OF VACCINE!

The WHO wrote: "Based on a WHO global survey conducted on 15 May 2009, a maximum of 4.9 billion doses could be produced in 12 months, but only if several assumptions are met. i) First, the full global production capacity is used for this vaccine production. ii) Second, production yield expectations for the influenza A (H1N1) vaccine are similar to those for seasonal vaccines. iii) Third, each manufacturer uses "dose sparing" for the vaccine formulation, i.e. the vaccine should use a smaller amount of active ingredient. A more conservative estimate of global vaccine production capacity is at least 1 to 2 billion doses per year. The number of people who could be vaccinated is not known until it is determined whether one or two doses of the vaccine are needed to achieve protection"^[16].

DOSIS-SPARE PRINCIPLE AND NEW CELL SUBSTRATE

In order to also achieve large vaccine quantities quickly, in contrast to the production of seasonal vaccines, the dose-saving principle was used for vaccine production (Note. Influenza vaccines are usually obtained by inoculating the virus strain of the embryonated chicken egg), i.e. smaller quantities of the "active ingredient" were used. The smaller quantity was compensated for by adding so-called adjuvants ("auxiliary substances"), which usually exert an immunostimulatory effect.^[17] (the above-mentioned AS03 in the case of swine flu). Since the number of chicken eggs available worldwide cannot supply the required vaccine quantities, other "cell substrates" for influenza vaccine production, such as Vero cells (monkey kidney cells), have been sought in the meantime.^[18]. However, these "cell substrates" harbour certain "biological safety risks", which need to be addressed in great detail^[19] and therefore - in my view - only "authority-known" cell substrates should be used, which is the case with Vero cells.

CONCLUSION: From the swine influenza (A/H1N1) virus outbreak (based on platform 2) at the end of 2008/ 2009 to the approval of the first vaccine in September 2009: 10-11 months.

OUTLOOK.

So when we hear these days that vaccines to protect against SARS-CoV-2 infection could be available in about (or maybe less than) 12 months, this would be an incredible speed and, in my view, more achievable with nucleic acid-based vaccines (see platform 3 in the list above), as possibly either preclinical safety reviews could be available quickly or, due to the urgency, these studies could run in parallel and one could therefore move quickly into the clinical phase. Another advantage of using this platform to produce vaccines would be the relatively quick availability of a large number of vaccine doses, as these can be produced directly and do not have to be extracted from, for example, chicken eggs or other cell substrates.

The US company Moderna, Texas (USA), has already started a first clinical trial with an m-RNA* of SARS-CoV-2 (which codes for the SARS-CoV-2 spike protein) on 3 March 2020.

(* "the mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of 2019-novel coronavirus (nCoV)", https://www.clinicaltrials.gov/.)

It is certainly a correct strategy to develop in parallel different vaccines produced on several platforms (all three mentioned) so that the vaccines with the best protection and safety profile and also sufficient quantities of vaccines could be available.

From the short time it took to produce the swine influenza (A/H1N1) virus vaccine, one cannot really extrapolate to the production of the SARS-CoV-2 vaccine, as many manufacturers worldwide were already licensed to produce seasonal influenza virus vaccines and also had a corresponding vaccine development programme (to ensure good manufacturing practice, preclinical, clinical and regulatory production) and "know-how". The development of the Ebola vaccine, on the other hand, broke new ground, which probably also reflects the longer period of time needed for production.

Since there are currently also numerous vaccine candidates for the development of SARS-CoV (not SARS-CoV-2) in the "pipeline".^[20]there may also be an opportunity to use/adapt these for SARS-CoV-2 vaccine development to save time.

References.

1. 1] Milestones of the last 70 years in the health sector, http://www.euro.who.int/de/about-us/organization/who-at-70/milestones-for-health-over-70-years, accessed 23.03.2020.
2. 2] RKI: https://www.rki.de/DE/Content/Infekt/Impfen/ImpfungenAZ/Unspezifische_Effekte_Impfungen.htm accessed 22.02.2020.
3. 3] Nathan Wolfe: "Die Wiederkehr der Seuchen". Rowohlt Verlag GmbH, Reinbek, Hamburg, ISBN: 978 3 498 073736 3, 2012. (Original edition: "The Viral Storm. The Dawn of a New Pandemic Age", Times Books, Henry Holt and Company, New York, 2011).
4. 4] Paules CI, Marston HD, Fauci AS.2020. Coronavirus Infections-More Than Just the Common Cold. AMA. 2020;323(8):707-708. doi:10.1001/jama.2020.0757, https://jamanetwork.com/journals/jama/fullarticle/2759815, accessed 18.02.2020.
5. 5] Op cit 3.
6. [6] Vaccine development in general, https://www.gesundheitsindustrie-bw.de/fachbeitrag/dossier/impfstoffentwicklung, accessed 22.03.2020.
7. 7]Wu F, et al. Nature, 2020 Mar. PMID 32015508, A new coronavirus associated with human respiratory disease in China, accessed 22.03.2020.
8. 8]PEI: What are coronaviruses: https://www.pei.de/SharedDocs/Downloads/DE/newsroom/dossiers/coronavirus.pdf?__blob=publicationFile&v=10, accessed 22.03.2020.
9. 9]Pharmazeutische Zeitung (13/2017) online: Vom Hühnerei zur Gentechnologie, https://www.pharmazeutische-zeitung.de/ausgabe-132017/vom-huehnerei-zur-gentechnologie/, accessed 22.03.2020.
10. 10] Chen, W., Strych, U., Hotez, P.J. et al. The SARS-CoV-2 Vaccine Pipeline: an Overview. Curr Trop Med Rep (2020). https://doi.org/10.1007/s40475-020-00201-6 https://link.springer.com/article/10.1007/s40475-020-00201-6 , accessed 22.02.2020.
11. 11]Hess RD, et al. "Ebola-Expedited Pathways for Drugs and Vaccines in Europe: The EMA Perspective." Regulatory Focus. July 2015. Regulatory Affairs Professionals Society.
12. 12] EMA, PRIME: Priority Medicines, https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines , accessed 22.03.2020.
13. [13] PEI: First Ebola vaccine approved worldwide: https://www.pei.de/DE/newsroom/hp-meldungen/2019/191113-erster-impfstoff-schutz-vor-ebola-zulassung-in-eu.html , accessed 22.03.2020.
14. [14] Dos Santos G, Seifert H.A, Bauchau V. et al. "Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt". Drug Saf 40, 693-702 (2017). https://doi.org/10.1007/s40264-017-0532-3, https://link.springer.com/article/10.1007%2Fs40264-017-0532-3#citeas, accessed 22.03.2020.
15. [15] Op cit 14.
16. [16] WHO, Vaccines for pandemic influenza A (H1N1), 2009. https://www.who.int/immunization/newsroom/H1N1_vac_q_a_16709.pdf , accessed 21.03.2020.
17. 17] Hess RD & Gosh P 2009. "Vaccines: preventive and therapeutic vaccines and adjuvants on the rise". J for Clin Studies, July 2009: 40-43.
18. Current Status of Development and Evaluation of Vero Cell-Derived Vaccines https://www.who.int/immunization/research/meetings_workshops/Otfried_Kistner.pdf ,, accessed 24.03.2020.
19. 19] Hess RD et al. 2012. "Regulatory, biosafety and safety challenges for novel cells as substrates for human vaccines" Vaccine Vol 30, issue 17, 2012.
20. [20] WHO, https://www.who.int/blueprint/priority-diseases/key-action/list-of-candidate-vaccines-developed-against-sars.pdf, accessed 22.03.2020