An employee supervises the aseptic packaging line of vials containing the COVID-19 vaccine candidate "AZD1222" (Rome, September 2020) -
© Vincenzo Pinto / AFP (via The Conversation)
The speed of development of vaccines against Covid-19 marks an absolute record in the history of vaccination, according to our partner The Conversation.
However, this feat does not necessarily herald a vaccine revolution that would allow the rapid development of vaccines against any pathogen.
The analysis of this phenomenon was carried out by Éric Muraille, biologist, immunologist, senior researcher at the FNRS, Université Libre de Bruxelles (ULB).
The World Health Organization (WHO) estimates that vaccination alone prevents about 3 million deaths worldwide each year.
Along with access to drinking water, this is the public health measure that has the greatest impact in terms of reducing mortality.
To deal with the Covid-19 pandemic caused by the emerging SARS-CoV-2 coronavirus, two main avenues have been explored: that of antiviral treatments, and that of vaccines.
While the Solidarity clinical trial, set up by the WHO to help find an effective treatment against Covid-19, was unsuccessful, three vaccines against SARS-CoV-2 were developed during the year 2020: BNT162b2 (BioNTech / Pfizer), mRNA-1273 (Moderna), ChAdOx1 nCoV-19 (Oxford / AstraZeneca).
In a few months, they could be tested in animals and validated by clinical trials in humans, which constitutes an absolute record in the history of modern vaccination.
Previously, it was considered that it took an average of 8 years to have an effective and safe vaccine.
How is this success explained?
Does he announce a new vaccine revolution, which would allow the development of vaccines against any pathogen?
The reality is more nuanced.
Covid-19 vaccines: the recipe for success
Attenuated, inactivated, adjuvanted subunit vaccine, viral vector, RNA ... Faced with the health emergency due to the rapid spread of SARS-CoV-2, all the vaccine technologies available were used without preconception to try to develop a vaccine, the aim being to reduce the risk of failure.
All the stages of development and validation were also linked, without the slightest pause.
This strategy of “all at the same time”, financially very costly and risky, was only possible thanks to a massive investment on the part of the States.
The US government has so far invested, through
Operation Warp Speed
, more than $ 18 billion to finance the development of vaccines against Covid-19.
An impressive figure, but which remains negligible given the estimated cost of the Covid-19 epidemic for this country.
In the event that it would be brought under control at the end of 2021, experts estimate that it will then have cost the United States between 3,000 and 16,000 billion dollars.
This massive investment will not only benefit the management of the SARS-CoV-2 pandemic.
In particular, it made it possible to validate the use in humans of RNA vaccine technology, which has several major advantages.
This technology makes it possible to develop a vaccine directly from the genetic sequence of the pathogen, without going through its culture or the production by genetic engineering of its proteins, which represents a considerable saving of time.
In mice, this technology has made possible the development in a few months of protective vaccines against viruses such as the H1N1 influenza virus or the Ebola virus.
It makes it possible to consider producing vaccine candidates to deal locally with emerging infectious agents before they spread and constitute a pandemic risk.
Finally, it also paves the way for personalized vaccines against tumors or autoimmune diseases.
These therapeutic vaccines, produced specifically for a single individual, would revolutionize immunotherapy.
Successes, but also many failures
This success and these hopes should not, however, make us forget that there are more than 1,400 pathogens infecting humans and that new ones emerge each year.
More than a century has passed since the discovery of vaccination by Louis Pasteur, but in that time frame, we have only been able to produce effective vaccines against less than thirty infectious diseases.
Louis Pasteur - rabies vaccination in Mr Pasteur's laboratory © Wikimedia CC BY-SA 4.0
Of course, we don't need vaccines against all pathogens.
Many cause only mild pathologies and many infections are preventable with simple prophylactic measures.
Nevertheless, we have suffered repeated failures for decades in the face of several pathogens representing public health priorities.
The causes of these failures are multiple.
One of them is based on the vaccine financing model.
Complex and laborious, it often involves numerous public-private partnerships.
However, the potential market for certain vaccines may be deemed insufficient by private investors.
For example, when the pathogen infects only a small number of individuals or has a limited geographical distribution.
But money is not everything: considerable investments have been made to fight the human immunodeficiency virus (HIV) responsible for AIDS, the bacterium
Mycobacterium tuberculosis
(also known as "Koch's bacillus"), responsible for tuberculosis or the protozoan parasites
Plasmodium
(cause of malaria, or malaria), responsible between them for more than 2.5 million deaths per year.
However, these investments have still not made it possible to develop vaccines with satisfactory efficacy.
First hope, a vaccine against malaria, the RTS vaccine, S / AS01 (Mosquirix, GSK), showed significant but partial protection in young children in 2015.
Why such difficulties, even when the resources allocated to research for new vaccines are considerable?
Will new vaccine technologies, such as RNA vaccines, change this situation?
Technical obstacles to vaccine development
Upon detection of a pathogen, the immune system responds rapidly with an innate response, mediated in particular by mucosal cells and macrophages.
To infect the host, a pathogen must be able, at a minimum, to partially escape this stereotypical response, which is not specific to a given invader.
The development of an adaptive, pathogen-specific, lymphocyte-mediated response most often allows the immune system to eliminate the infectious agent and to acquire long-lasting immunity against it.
The principle of vaccination is to copy this adaptive immunity, which develops following a natural infection.
All vaccines therefore contain information on the structure of the pathogen, which is called “antigens” (a term designating any element foreign to the body capable of triggering an immune response).
Depending on the type of vaccine, the antigens may be present in the form of, for example, virus proteins (adjuvanted subunit vaccine) or viral genetic material (vector vaccine, RNA vaccine).
They are essential to induce the development of specific lymphocyte populations of memory which will make it possible to control and eliminate the pathogen.
When it is desired to develop a vaccine against a pathogen, the identification of vaccine antigens is therefore considered to be a prerequisite.
The genome of the majority of viruses includes only a few dozen, or even a few hundred genes.
It is therefore quite easy to identify those corresponding to the antigens most exposed to the immune system, such as the “spike” protein of SARS-CoV-2.
In bacteria and protozoa, things are different: their genome contains several thousand genes.
And that of some parasitic worms in the tens of thousands.
Therefore, identifying vaccine antigens for these highly complex pathogens can require very long work.
Life cycle of Plasmodium falciparum, agent of malaria or malaria © Centers for Disease Control and Prevention (via The Conversation)
In addition, some pathogens have complex life cycles within their host (the organism they infect).
They can turn during infection.
These changes may be accompanied by the expression of different antigens at each stage of the cycle.
This further complicates the identification of the most appropriate antigens to develop an effective vaccine.
This is the case, for example, with the protozoa
Plasmodium
, agents of malaria, part of the life cycle of which takes place in the Anopheles mosquito and the other in humans.
The mosquito vector infects humans with a first form of the parasite, which will multiply in liver cells and transform into a second form.
This will infect the red blood cells and multiply there in a third form.
Each of these forms has distinct antigens.
The problem of escaping the immune response
Beyond these difficulties in identifying vaccine antigens, many pathogens have also acquired during evolution mechanisms of escape from the adaptive immune response.
These mechanisms allow them to persist in the host for long periods of time, sometimes throughout the host's life, which increases their chances of transmission.
It is these escape mechanisms, which rely mainly on antigenic variation (antigens change over time, which thwarts the development of adaptive immunity), stealth or neutralization of the immune system, which sometimes makes it nightmarish. the development of a vaccine.
The genome of RNA viruses evolves at an extremely rapid rate.
Indeed, when these viruses multiply and copy their genetic material, they make many mistakes, which leads to the emergence of a large population of variants.
This great diversity can make it impossible to identify vaccine antigens that would make it possible to target the entire population.
In this respect, the case of the influenza virus responsible for influenza is emblematic.
Its genome can evolve gradually not only by mutations (this phenomenon is called “antigenic drift”), but also by the exchange of whole genes with other viruses of the same species (reassortment).
Influenza vaccines cannot target all of these antigens;
they only contain the most common.
As a result, they do not protect against all variants of the virus and their composition must be updated each year to take into account the antigens present on the viruses mainly in circulation.
Evolution of the influenza virus, agent of influenza. Difference between reassortment (Antigenic Shift) and antigenic drift (Antigenic Drift) © The Conversation
Certain pathogens are even capable of varying the most exposed antigens on their surface at such a rate that they generate a large population of variants within the infected host itself.
This is for example the case of the bacterium
Helicobacter pylori
, which causes peptic ulcers, or of the protozoan
Trypanosoma brucei
, the agent of sleeping sickness.
This permanent variability prevents the adaptive immune system from targeting the entire population of invaders, and therefore neutralizing them.
Other pathogens can make themselves almost invisible to the immune system by directly neutralizing its activation pathways or by modifying host cells to build cellular reservoirs that isolate them from the immune response.
Viruses of the
Herpesviridae
family
, such as cytomegalovirus, block the presentation of their antigens to the immune system.
The bacterium
Mycobacterium tuberculosis
disrupts the microbicidal mechanisms and modifies to its advantage the metabolism of the macrophages which it infects.
Partial or total suppression of the immune system, which results in a weakening of the host's immune system (immunosuppression), is another effective strategy for ensuring the persistence of the pathogen.
It is likely to invalidate all vaccine strategies.
The measles virus reduces the diversity of the antibody repertoire of its host and destroys the protective immune memory acquired against other pathogens, causing "immune amnesia".
Infection with
Plasmodium
protozoa
induces the production of immunosuppressants, molecules that affect the entire immune system and permanently reduce the host's ability to respond to infections and develop immunity following vaccination.
And nothing prevents certain pathogens from accumulating numerous escape mechanisms.
HIV, for example, has a very high mutation rate, a source of many variants, is able to integrate for a long time into the genome of the cells of its host, which makes it undetectable, and destroys CD4 T lymphocytes, this which ultimately causes deep and irreversible immunosuppression.
This combination of escape mechanisms has so far challenged all vaccine strategies.
Our "Vaccines" file
The success of Covid-19 vaccines should not blind us
Certainly, vaccination techniques have made considerable progress in recent decades, thanks in particular to a better understanding of the immune system and to advances in molecular biology techniques.
Despite everything, it should be noted that we were "lucky" to be confronted, with the SARS-CoV-2 coronavirus, with a relatively "simple" pathogen.
Indeed, if the new vaccine platforms allow rapid production of vaccines from the genetic sequence of a pathogen, it is unlikely that this empirical approach is sufficient to deal with complex microorganisms, or those having mechanisms of escape from the adaptive immune response.
To counter pathogens of this type, it will undoubtedly remain necessary to finely characterize their multiplication cycle as well as their interactions with the host's immune system, to reveal the defect of their armor.
This can prove to be laborious and involves the funding of fundamental research without a priori over the very long term, as well as close cooperation between immunologists and microbiologists.
It should also be borne in mind that having an effective vaccine does not dispense with monitoring the genomic evolution of the pathogen concerned.
Indeed, the relationship between a pathogen and its host follows a Red Queen type dynamic: pathogens constantly evolve in response to the selection pressures of their host, as shown by the acquisition of resistance to antibiotics, antivirals and certain vaccines.
Many mutations of SARS-CoV-2 have already been documented.
Will the selection pressure generated by Covid-19 vaccines select variants capable of escaping them?
The future will tell.
One thing is certain, monitoring and understanding the interactions between the pathogen and its host is important in anticipating these potential problems.
Finally, a vaccine is only effective if it is used.
However, vaccinating the world population is a challenge, not only logistically, because of the poor infrastructure in many regions, but also because the level of vaccine hesitation is high.
To the point that vaccine hesitation was identified by the WHO in 2019 as one of the 10 main threats to global health.
In conclusion, it therefore remains imperative to invest massively in health systems, scientific communication and above all, in the prevention of pandemics, by acting on the socio-economic conditions favoring their emergence.
Because it is now obvious that preventing these crises costs much less than to undergo them.
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This analysis was written by Éric Muraille, biologist, immunologist, senior researcher at the FNRS, Université Libre de Bruxelles (ULB).
The original article was published on The Conversation website.
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