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Authors: Dr Daniel Maller

Contributors: Dr Irène Fermont

Published date: 10 Jan 2022

Ref: 0717

In March 2020, the stunned world is feeling the effects of the first wave of Covid 19: overwhelmed hospitals, and worrying lethality. It will be the first confinement, and state of health emergency, with its share of instructions and restrictions. December 2020 sees the dawning of hope for a solution, with the announcement of the development of a vaccine based on revolutionary technology, both in terms of design and speed of implementation. Pfizer-BioNTech and Moderna laboratories begin to deliver their precious elixir. Israel begins an active vaccination campaign at the end of December 2020, and seems to have defeated the coronavirus at the end of March 2021.


But it was a Pyrrhic victory, with virus mutations making mutants more and more contagious. Other waves will follow one another, to the rhythm of the Greek alphabet: alpha, beta, delta, and omicron for the latest. In this context of endless day and time loop, it is essential to understand why vaccination remains an effective weapon, despite appearances that may possibly suggest otherwise.


To do this, we will assess the concept of vaccine efficacy, in terms of contamination and pathogenicity, in order to understand the options that, to date, are available to scientists in order to propose a coherent vaccine strategy.


“We need to be aware that even triples vaccinated people are capable of transmitting the disease,” said Dr. Uğur Sahin, CEO of the company BioNTech which, together with Pfizer, has developed one of the most effective vaccines against Covid-19. This statement, published in Le Monde on 20 December 2021, does not mean that this vaccine, which does not prevent contamination by vaccinated subjects, would be a bad vaccine. We will explain it.


Certainly, there are vaccines that generate a response capable of completely eliminating the virus from the body, thus eliminating the risk of contamination. Such "sterilizing immunity" has been obtained with the smallpox vaccine. After killing more than 300 million people during the 20th century, this disease was officially eradicated in 1980, thanks to massive vaccination campaigns. Likewise, the measles vaccine prevents both the onset of the disease and its transmission.


Such a definitive immune response, however, is not necessarily essential to stem the spread of an epidemic. As the Scientific American Journal reminded in January 2021, a vaccine that is not fully effective in preventing the transmission of a pathogen, can nevertheless hinder its spread in the general population.


An undeniable interest of non-sterilizing vaccines

Many vaccines have shown their value without conferring sterilizing immunity. One example is the hepatitis B virus vaccine, whereby the immune system of vaccinated individuals sufficiently reduces the impact of the pathogen to prevent disease, even though the pathogen may persist in the body and potentially infect other people.


Likewise, no sterilizing immunity for the vaccine against rotavirus, which causes diarrhea and vomiting in infants and young children. Vaccination limits the replication of the pathogen, but does not prevent it completely. It therefore does not protect against mild forms of the disease, but by reducing the viral load of an infected individual, it decreases the risk of transmission.


As for the anti-Covid vaccines currently in use, they also reduce transmission between individuals, but their main short-term benefit lies elsewhere: if they do not always prevent the occurrence of the disease, they clearly reduce the probability of appearance of severe forms. Depending on their vaccination status, vaccinated subjects are thus up to twenty times less likely to end up in critical care units than unvaccinated individuals, all variants combined. However, this probability does not depend solely on vaccination. As we know, age, sex (men are more vulnerable) and comorbid factors, not to mention genetic factors, are also involved.


In September 2020, two researchers at the Max-Planck Institute in Leipzig, showed in a Nature article that a higher likelihood of developing a severe form of Covid-19 was linked to genes inherited from Neanderthals. Virtually absent in Africa, they are worn by around 16% of the population in Europe, and around 50% in South Asia. These legacies of a "brief" common history with the Neanderthals come tens of thousands of years later in the memory of Homo sapiens. As if to remind him that, in his confrontation with viruses, there are genetic hazards over which he has no control.





The immune system is an extremely complex machinery whose role is to protect the body from attacks, whether traumatic or infectious (parasitic, bacterial, mycotic, viral).









This system is capable of reacting immediately, either by an inflammatory reaction and / or the synthesis of antibodies (humoral immunity) capable of neutralizing the infectious agent, or by the action of killer cells (cellular immunity) capable of destroying infected cells.


But it can also react in a delayed manner, by stimulating memory cells capable of very rapidly producing clones of antibody-producing lymphocytes and clones of killer lymphocytes. Vaccination, like natural infection, contributes to the establishment of this memory immunity, which a new contact with the infectious agent or a vaccination booster will quickly activate.


Vaccination stimulates the whole system, but in practice and routinely, the level of stimulation can only be assessed by measuring the circulating antibodies, i.e. the immediate humoral response. The duration of vaccine immunity is therefore extrapolated by observing the occurrence of the disease in the vaccinated population and, on the other hand, by measuring the circulating antibodies. The techniques for studying memory cells as well as those for the cellular immune response exist, but are very sophisticated and are still in the field of research.
























Regarding vaccination with mRNA vaccines, it turns out that the antibody level drops rapidly three to four months after the second dose, then rises sharply after the third dose, but for a period that has not yet been precisely determined. In Israel, the booster (third dose) significantly affected both the incidence rate and the number of hospitalizations and deaths during the Delta variant wave. These findings are the basis for the injection of a fourth dose, to combat the current wave of the Omicron variant.


What about delayed cellular and humoral immunity? (2)

It being understood that the antibody level decreases significantly over time, and that the new variants are often less sensitive to it, it must be admitted that the immediate humoral immunity obtained with current mRNA vaccines will no longer sufficiently protect against viral circulation and mild forms of the disease. Regarding the Omicron variant, which has a significant number of mutations compared to previous variants, it is believed to be much more transmissible than Delta, but less pathogenic.


Indeed, the first data from the Omicron wave (South Africa, Denmark, United Kingdom) show that protection against severe forms of the disease continues. There is obviously a decorrelation, for the moment incontestable, between the number of positive tests and the number of serious cases. The next few weeks will confirm - or not - this finding. But it will remain difficult to specify whether this very contagious Omicron variant is indeed less virulent, or if it has been defeated, that is to say if the frequent occurrence of serious forms of the disease in predominantly vaccinated populations, was blocked by special forces regiments of delayed immunity (memory immunity).



The graph below shows the number of new severe cases in December 2021 in Israel. The difference between vaccinated and unvaccinated people is obvious. There was a slight upturn in cases in the last week, probably corresponding to the arrival of the Omicron variant, or to the first effects of the loss of efficacy against the Delta variant of the booster started in July, or to the conjunction of the two phenomena. However, the difference remains clearly visible.

In France, the resuscitators who speak publicly, all indicate the enormous prevalence of unvaccinated people in intensive care (70 to 90% of cases depending on the region), and on 5 January 2022, the virtual exclusivity of the Delta variant in these patients.


The DREES (Department of Research, Studies, Evaluation and Statistics) gives the following figures for the week of 13 to 19 December 2021: (3)

• Out of 1 million vaccinated subjects, 1.5 individuals were admitted to intensive care each day on average;

• Out of 1 million unvaccinated subjects, 26 individuals were admitted to intensive care.


This shows that seventeen times more unvaccinated people have been hospitalized in an intensive care unit, than people with a complete vaccination schedule.


These figures also confirm a very high level of vaccine protection (around 94%) against severe forms of the disease - on the other hand, they are less effective in terms of preventing the spread of the virus. In fact, everyone knows people who have been properly vaccinated but who have tested positive for Coronavirus, and who however only present asymptomatic or very mild forms of the disease.


If we go back to the chronology: the vaccine injection (usually 2 injections) protected us against the Alpha virus, the Coronavirus originating in China. The first vaccine booster (dose 3) then acted as a lifeline against the Delta variant. Each time, the extra dose gives a margin of safety on the new variants to protect against the severity of the infection. That is why we expect the fourth dose to now protect us against the Omicron variant.



It is found that mRNA vaccines greatly stimulate humoral immunity and circulating antibodies, but we have little proven data on the effectiveness of these vaccines on the memory response, and more specifically on the cellular memory response. A few months ago, publications showed that the vaccine memory response with two doses was 1.5 times lower than natural immunity.


Natural infection stimulates the immune system much more widely, triggering a more varied synthesis of antibodies, whereas mRNA vaccines only cause the synthesis of anti-spike antibodies. Natural immunity therefore provides a larger reservoir of antibodies which appears to be stable over time. An article published in Nature showed that natural immunity lasted for at least 18 to 24 months (we have no more time to look back on the Covid-19 pandemic). However, it should be noted that we sometimes see the reinfection, by new variants, of previously infected people.


Recombinant protein vaccines

We do not know whether memory immunity wanes after injection of mRNA vaccines. We do know, however, that other recombinant protein vaccines, such as hepatitis B vaccine, induce very robust memory immunity. We can therefore hope, by analogy, that recombinant protein vaccines like that of Novavax or Sanofi will be able to function for several years, ideally up to 10 years! This is an extremely favorable scenario, but it is still premature to predict that it will be so.




There is currently an international consensus on the need to intensify vaccination in insufficiently vaccinated or unvaccinated populations.


Five to six months after the injection of the first two doses of the vaccine, there is a decline in the immunity that they had previously conferred. In Israel, the wave of the Delta variant was successfully tackled, thanks to a third dose of vaccine from the end of July 2021. This decision to administer a booster just a few months after the primary vaccination was bold, but it has proved its worth in greatly reducing the risk of severe cases in vaccinated people.


After some hesitation, and in view of the results obtained in Israel against the Delta variant, the American FDA, Europe, and many countries in the world, are now offering a third dose for all, this time in order to slow the wave of Omicron and to protect as many people as possible from severe forms of Covid19. In this emergency strategy, it seems reasonable not to wait more than three months for a vaccination booster, as recommended by the HAS (Haute Autorité de Santé).


Today, 5 months after the administration of the booster, Israel is again seeing a decline in humoral immunity (antibodies). The repetition of this scenario explains why some experts advocate a fourth dose injection to dominate the Omicron wave.


However, this is not everyone's opinion. Indeed, the Omicron differing more from the Delta than the latter differed from the Alpha (the viral form circulating at the very beginning of the pandemic), and the current anti-Covid vaccine continuing to effectively protect against severe forms of the disease - even if it only avoids contamination at 33% - other experts recommend waiting for the development of a more specific vaccine which, as such, will be more effective.


Ultimately, it is the speed of the contagion and the assessment of the severity of this new wave that, as well as the ability to produce a more specific vaccine quickly and in large quantities, will guide the choice of vaccine strategy.


On 4 January 2022, the Israeli authorities decided and gave access to a fourth dose of vaccine to all people over 60 years of age, as well as to people at risk, immunocompromised or suffering from co-morbidities. A study conducted at Sheba Hospital in Ramat Gan shows that antibody levels increase five-fold after the fourth dose. Israel, the first country in the world to adopt this strategy, is once again taking the lead. This initiative is already being viewed with interest by other countries.



After the immense hope aroused by the results of the first vaccination campaigns, one can understand the disappointment at the decline in immunity earlier than expected, forcing us to repeat the vaccination. In fact, the coronavirus responsible for Covid 19, with its many variants, forces us to constantly rethink vaccination strategies and decisions on health restrictions. However, although vaccines have not yet ended the pandemic, they have already saved millions of people from hospitalization and death.


It is clear that we still need to improve the effectiveness of mRNA vaccines, in order to achieve protection that is more durable and less susceptible to virus mutations. However, this should not prevent us from understanding the extraordinary scientific and technological advance that they represent, and the upheavals of tomorrow's medicine that they herald in the fields of vaccination, treatment of AIDS, malaria, cancerous conditions, and many other diseases to date without known therapy.


The development of new vaccines, and the emergence of new treatments that are very effective in preventing severe cases and death in at-risk patients, Pfizer's Pavloxid and Merck's Molnupiravir, give us more reasons to be hopeful regarding a victory over the pandemic.


Finally, faced with the favorable development in terms of severity of the Omicron wave in Denmark and Great Britain, despite the high number of people tested positive, some reputable scientists have dreamed that it will be the last wave, the one which will finally confer the collective immunity so hoped for, and thus bring the end of the pandemic. We will know in two months whether this optimistic scenario comes true.








  3. Covid-19 : la majorité des patients en réanimation sont bien non vaccinés (

  4. Baisse d’efficacité des rappels face à la vague Omicron : faut-il revoir la stratégie vaccinale ? (

relevance of the anti-covid vaccine-DM-IF-MB.jpg
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