Prof. François NR Renaud, Scientific Advisor
The Covid-19 outbreak brings us into the mysterious world of vaccines. It has to be said that an effective vaccine against the Sars-Cov-2 virus would be of great use in the fight against the new coronavirus.
By the way: What is a vaccine?
An “antigen” or, better yet, an “immunogen” is any molecular species that, when introduced into an organism, induces an “immune response”.
An immune response is a complex biological process that leads to the formation of recognition molecules that are either released in the serum, they are then called antibodies, or remain attached to the cells that gave rise to them, they are then cellular receptors. In the first case it is the humoral response, in the second case the cellular response.
This introduction is from my immunology course when I taught at the University.
It immediately set the tone: this course will be particularly difficult!
A bit of history
Thucidide (-465 -400/-395) had noticed that people suffering from the Athens “plague” could not get sick again or had only mild symptoms. Lady Montagu (1689-1762) introduced in Europe an Ottoman technique of inoculating cured smallpox crusts into healthy people to protect them against smallpox (variolization). Physician Edward Jenner (1749-1823) protected a child from smallpox by inoculating him with vaccinia, a virus similar to smallpox. But it was Pasteur (1822-1895) who developed the principle of vaccination by protecting little Joseph Meister against rabies using rabies marrow deactivated by aeration.
What is a vaccine?
Vaccination therefore consists of injecting a healthy person with killed or attenuated microorganisms, or even fragments of the organism, in order to initiate the specific protective immune response. During the first contact, also called primary response, antibodies are formed, first IgM and later IgG. On the second contact, the secondary response produces a large number of antibodies capable of stopping the infectivity of the pathogenic microorganism. However, it should not be forgotten that the primary and secondary responses also take place on the cellular side. It is this cellular immunity that is the main factor in the responses against viruses.
Conventional vaccines
Vaccines are usually said to consist of live microorganisms that are attenuated (oral polio vaccine), killed (injectable polio vaccine), or their fragments (influenza). This concept has evolved considerably since the 1960s. The recombinant DNA technique consists of having a virus gene expressed in a yeast for example (hepatitis B) or of artificially synthesizing capsular antigens (Streptococcus pneumoniae).
Currently, in France, 11 vaccines are obligatory: (January 1, 2018) Diphtheria, tetanus, poliomyelitis + pertussis, measles-mumps-rubella, hepatitis B, Haemophilus influenzae type B bacteria, S. pneumoniae and meningococcus C.
Vaccines against Covid-19
In the case of COVID-19 the humoral response, i.e. the formation of antibodies released in serum, was general in the vast majority of infected patients. The antibodies are directed against the nucleocapsid and spike glycoprotein. Some of these antibodies are neutralizing (anti RBD binding site) while others may participate in the development of severe forms of the disease. Cellular responses have also been demonstrated, some of which appear to be protective (Th1 lymphocytes) while others may play a role in aggravating clinical signs (Th2 lymphocytes). These observations show us how difficult it is to choose the right vaccine, as immune responses do not always result in protection!
According to WHO, 130 candidate vaccines have been developed worldwide, 19 of which are undergoing clinical evaluation.
In France, some thirty teams are working on this theme. At Institut Pasteur, the attenuated measles vaccine into which the SARS-Cov-2 genes have been introduced is capable of producing an anti-Covid-19 immune response. In Lille (Centre infection et immunité) in Lille) the pertussis vaccine is the vector, in Créteil (Institut de recherche vaccinale) monoclonal antibodies present the virus antigens, while at the “Institut pour l’avancée de Biosciences” in Grenoble, virus-sized lipid droplets carry the viral antigens.
In the rest of the world, two teams – one at Oxford University in the United Kingdom, in collaboration with the pharmaceutical company AstraZeneca, and the other composed of researchers from CanSino Biologics in Tianjin, China – have also developed “viral vector” vaccines.
A third group, BioNTech in Mainz, Germany, is developing an mRNA-based vaccine with the pharmaceutical company Pfizer. It is an RNA vaccine encoding the spike protein receptor binding domain. This followed long-awaited clinical trial results published by Moderna, a Cambridge, Massachusetts-based biotech company, which has developed a competing mRNA vaccine consisting of the entire spike protein, in collaboration with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.
The U.S. company Pfizer also announced on March 17 that it has partnered with the German company BioNTech to produce and distribute an mRNA vaccine to prevent CoV-2-SARS infection.
The different phases of vaccine development
A vaccine trial follows a codified process, with phases that have specific objectives. The results of one phase must meet defined criteria in order to proceed to the next. It is a rigorous and long process where each stage provides additional information. Thus, it takes many years to bring a vaccine to market (about 10 years). In the case of COVID-19, the very large number of teams and laboratories (and the financial resources that go with it) will most likely allow a vaccine to be developed in record time.
Preclinical trials
Vaccines are first studied in the laboratory and tested in animals.
Clinical Trials
Carried out in humans, they comprise 3 successive phases that correspond to different objectives.
Phase I (safety) aims to determine the safety of the vaccine candidate in humans: serious adverse effects, tolerance, immunogenicity (does the vaccine candidate generate an immune response?). Between 10 and 100 healthy volunteers.
Phase IIA. Trials are carried out on a very small number of volunteers. The tolerance and safety of the vaccine candidate, its immunogenicity, and the optimal dose of vaccine to be used are still being tested.
Phase IIB, also known as “proof of concept”. Trials are conducted on a larger number of volunteers to determine whether the vaccine provides lasting protection against infection. The vaccine strategy is determined. Between 50 and 500 healthy volunteers.
Phase III (efficacy and benefits/risks). Trials are testing the benefit/risk ratio of the vaccine on hundreds, if not thousands, of people. It involves several thousand individuals (at least 30,000 over 2 years) from the target population. These central studies are used to define the conditions and precautions for vaccine use and, ultimately, to apply for marketing authorization from drug agencies. But beware, many vaccine candidates do not pass phase III!
Marketing
The Drug Agencies review all available evidence, authorize or deny marketing, and define the framework and conditions for the use of the vaccine.
When a vaccine is marketed, it enters the pharmacovigilance phase, sometimes called Phase IV. Patients and physicians are encouraged to report unreported side effects to the surveillance authorities (in France, the ANSM). This phase lasts as long as the vaccine remains on the market.
Currently 9 clinical trials are in phase 3. Among them, the vaccine developed by the German company BioNTech in partnership with the American laboratory Pfizer. The vaccine developed by the American biotech company Moderna and the Chinese laboratories Sinopharm and Sinovac (inactivated vaccines). As well as the project led by Oxford University in cooperation with the British pharmaceutical group AstraZeneca and the Chinese company CanSino.
As for the Russian vaccine Sputnik V (Adenovirus carrier), it has entered phase 3 but many doubt the validity of the previous steps!
Vaccine Acceptance
Anti-vaccine movements are multiplying. Between 25 and 30% of French people would refuse the anti-Covid vaccine! It should not be forgotten that vaccination protects the individual concerned but participates in the collective immunity by preventing the virus from circulating. This behavior is political in nature, calling into question the relationship between government and pharmaceutical laboratories. As a reminder, it was a study published in 1998 in the medical journal The Lancet that suggested a link between ROR vaccination (Measles, Mumps, Rubella) and the occurrence of autism in young children that set the ball rolling. The study turned out to be a ” fake” by its author Andrew Wakefield. The journal’s official denial and the many subsequent studies showing no link between vaccines and autism will not silence the fears. The fake study is still regularly cited by vaccine opponents today. No comment will be made on The Lancet magazine, which again this year has made headlines about a bogus study of the antiCovid drugs…
Conclusion
Contrary to what one might think, it is not enough to simply inject the deactivated pathogen to obtain a valuable vaccine. The antigens in the vaccine must elicit an immune response that produces neutralizing antibodies and/or cells that inhibit the pathogen without promoting the development of antibodies that are involved in the severe form of the disease or cells that aggravate clinical signs such as Th2 cells. In addition, the vaccine should not have any toxicity or delayed side effects. The tests are therefore drastic and must be respected, all the more so since in today’s world the smallest misstep can only fuel conspiracy theories and destroy all efforts aimed at our protection. Let’s not forget either that, in the case of Covid-19, the competition between the world’s major pharmaceutical laboratories has allowed an extremely rapid progress of research, beyond all expectations, nevertheless these laboratories must remain in the nails and be well differentiated from the sometimes inappropriate communication towards them by political leaders.
References
Les représentations médicales dans l’art.François LACROUX, François RENAUD. Document de travail sur l’art et la science.
Futura-sciences [1]
Professionnels vaccination info service [2]
Le monde : réalités biomédicales [4]
Nature [5]
Inserm, Dossier spécial Covid-19, #47, juillet 2020