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Why Can’t We Develop Vaccines Against All the Germs that Make us Sick?

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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 most significant impact in reducing mortality.

To face the Covid-19 pandemic caused by the emerging coronavirus SARS-CoV-2, two main avenues have been explored: antiviral treatments and 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 Nov-19 (Oxford / AstraZeneca).

In a few months, they could be tested in animals and validated by clinical trials in humans, which is an absolute record in modern vaccination history. 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

Attenuatedinactivated, 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 simultaneously,” 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 remains negligible given the estimated cost of the Covid-19 epidemic for this country. If it were brought under control at the end of 2021, experts estimate that it will 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 has 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 it possible to develop protective vaccines against viruses such as the H1N1 influenza virus or the Ebola virus within a few months. It makes it possible to produce vaccine candidates to locally cope with emerging infectious agents before they spread and constitute a risk of a pandemic.

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

However, this success and these hopes should not make us forget that there are more than 1400 pathogens infecting humans and that new ones emerge each year. More than a century has passed since the discovery of vaccination by Louis Pasteur. Still, we have only produced effective vaccines against less than thirty infectious diseases in this period of time.

Of course, we don’t need vaccines against all pathogens. Many cause only mild illnesses, 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 enabled the development of vaccines with satisfactory efficacy. The first hope, a vaccine against malaria, the RTS vaccine, S / AS01 (Mosquirix, GSK), has shown significant but partial protection for 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 detecting 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. Therefore, all vaccines contain information on the structure of the pathogen, which is called “antigens” (a term designating an 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, such as 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, identifying vaccine antigens is considered a prerequisite. The genome of most viruses comprises only a few dozen, or even a few hundred genes. Therefore, it is relatively 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.

Also, some pathogens have complex life cycles within their host (the organism they infect). They can transform 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. For example, this is the case of Plasmodium protozoa, agents of malaria, part of the life cycle of which occurs 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 the liver cells and transform into a second form. This will contaminate the red blood cells and bear there is 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. These escape mechanisms 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 result 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.

The case of the influenza virus responsible for the flu is emblematic in this respect. 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. Their composition must be updated each year to consider the antigens present on the viruses, mainly in circulation.

Specific pathogens are even capable of varying the antigens most exposed on their surface at such a rate that they generate a large population of variants within the infected host itself. For example, this is the case with the bacterium Helicobacter pylori, which causes peptic ulcers, or the protozoan Trypanosoma brucei, the agent of sleeping sickness. This permanent variability prevents the adaptive immune system from targeting the invaders’ entire population and therefore neutralizing them.

Other pathogens can make themselves almost invisible to the immune system by directly neutralizing its activation pathways or modifying host cells to build cellular reservoirs that isolate them from the immune response. Viruses of the Herpesviridae family, such as cytomegalovirusblock the antigens’ presentation to the immune system. The bacterium Mycobacterium tuberculosis disrupts the microbicidal mechanisms and modifies its advantage in the macrophages’ metabolism that it infects.

Partial or complete suppression of the immune system, which results in a weakening of the host’s immune system (immunosuppression), is another effective strategy for ensuring the pathogen’s persistence. It is likely to invalidate all vaccine strategies. The measles virus reduces the diversity of its host’s antibody repertoire and destroys the protective immune memory acquired against other pathogens, causing “immune amnesia.” Infection by Plasmodium protozoa induces the production of immunosuppressants, molecules that affect the entire immune system and permanently reduce the host’s ability to respond to conditions and develop immunity following vaccination.

And nothing prevents specific pathogens from accumulating numerous escape mechanisms. HIV, for example, has a very high mutation rate, a source of many variants, can integrate for a long time into the genome of the cells of its host, which makes it undetectable, and destroys CD4 T lymphocytes, which ultimately causes profound and irreversible immunosuppression. This combination of escape mechanisms has so far challenged all vaccine strategies.

The success of Covid-19 vaccines should not blind us.

Admittedly, vaccination techniques have made considerable progress in recent decades, thanks to a better understanding of the immune system and 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 the rapid production of vaccines from the genetic sequence, it is unlikely that this empirical approach is sufficient to deal with complex microorganisms or those having escape mechanisms for the adaptive immune response.

To counter pathogens of this type, it will undoubtedly remain necessary to finely characterize their multiplication cycle and 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 and close cooperation between immunologists and microbiologists.

It should also be borne in mind that having an effective vaccine does not dispense with monitoring the pathogen’s genomic evolution. 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 antibioticsantivirals, 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. For sure, monitoring and understanding the interactions between the pathogen and its host is important to anticipate 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 vaccine hesitancy is high. To the point, that vaccine reluctance was identified by the WHO in 2019 as one of the 10 main threats to global health.

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