September 2021. The French government is timidly launching the reminder campaign for the most vulnerable. Are concerned, at the time, the over 65s and people with comorbidities. Six months later, the result is in: more than 47% of French people have received a third injection of vaccine against Covid-19. At the same time, the epidemic wave swept across France – driven by the Omicron variant, which was more contagious than its Delta predecessor. While the number of contaminations has been falling for six days, it amounted to 334,260 new cases on Monday (average over seven days). In addition, the incidence rate decreased for the fifth consecutive day in all age groups under 60 years. However, older people are mostly vaccinated: among 65-74 year olds, 83% have had a booster dose and 77% among those over 75 years old. Many fragile people as well as caregivers received the third dose more than four months ago, but are they still protected?
Behind this question hovers that of the fourth dose. If some countries have taken the step – like israel – France is not yet ready to follow suit. On January 27, the Strategic Council for Vaccine Orientation declared that it was not in favor of it. The reason: the lack of data. “We need more hindsight to measure the durability of defense mechanisms following vaccination or infection”, comments to L’Express Yannick Simonin, virologist at Inserm in Montpellier. As a reminder, the vaccine is used to reboost the circulating antibodies (in the blood) which prevent infection and fight serious forms. If these antibodies disappear after four to eight months, what about cellular memory, too often forgotten? “Of course, the neutralizing antibodies are decreasing, but there is a cellular response which is beginning to be investigated and which could make it possible to control the serious effects over a longer period of time than the kinetics of the antibodies”, explains Hervé Fleury, virologist and professor emeritus at the CNRS and at the University of Bordeaux.
Immune memory is triggered by an infection, especially if it is symptomatic – the more severe the form, the more the immune system is involved and the stronger the memory – but also by vaccines. Yannick Simonin makes the following observation: “Immunity is made up of two main parts: humoral immunity, ensured by the production of antibodies, and cellular immunity, which will play a memory role and protect us from more severe forms of disease.” Immune memory involves B and T cells, which remember antigens to attack. CD8 T lymphocytes are responsible for identifying antigens on the surface of infected cells (produced by a virus, for example) and destroying them. “Even if we have circulating antibodies which disappear after three, four, six months, we may still have our CD8s which would protect us from serious forms”, continues Hervé Fleury.
The specialist adds: “The idea, in the long term, is to know if the CD8 persists after a year or two, and if this is the case, we will no longer need a booster injection before a year. or two.” However, several uncertainties remain about cellular immunity: for example, is it capable of protecting us alone against serious forms? Scientists seem divided on this issue. For Olivier Schwartz, head of the Virus and Immunity unit at the Institut Pasteur, if “humoral immunity plays a role”, it would not be sufficient on its own, he believes. An opinion that Yannick Simonin does not entirely share: “After the second dose, we had an antibody level which was very low vis-à-vis Omicron, but we always benefited from cellular protection.” According to the virologist, it is possible to have cellular protection that protects us against severe forms even if humoral protection is not detectable.
Gray areas remain around cellular memory
Francesco Salvo, head of the Bordeaux pharmacovigilance center, describes the mechanism that takes place a few months after vaccination or infection: “The antibody level drops gradually, over time we could be less protected against a infection. When the virus arrives in the body, it does not find enough antibodies and it begins to replicate, but just long enough to reactivate the cellular memory already present.” Once it has been reactivated, antibodies against the virus are produced, which prevents its replication and therefore reduces the risk of inducing a serious infection. Until then, researchers had focused more on the production of antibodies, because cellular immunity requires more time to reveal its secrets. “We always have data that is out of step between antibodies and cellular immunity,” notes Yannick Simonin. However, the question of cellular memory is central.
“The problem is knowing which protection is more important: is it circulating antibodies or CD8s”, adds Hervé Fleury. Furthermore, the type of cellular memory can vary whether it is from a vaccine or from an infection.” Cellular memory from a vaccine is more standardized. With three injections of the vaccine, it is hoped to trigger a memory cell sufficiently reactive in the long term against serious forms of infections due to variants comparable to those that we know”, maintains Francesco Salvo. Before launching a second booster campaign, it is important to have reliable data concerning the duration of effectiveness of the third injection. If the latter provides more antibodies against the Omicron variant, the impact of cellular immunity is still difficult to assess. “If the antibodies drop after a few months, the cellular memory is more stable over time”, continues Yannick Simonin.
How long can cellular immunity be effective? “For some infections, it can last several years. Regarding Covid-19, we still have very little perspective. We will have to wait to obtain more data”, admits the virologist. The duration of cellular immunity would also vary depending on the virus. “Against Covid-19, we have an immunity that lasts a long time. More than a year later, the memory cells are there and can be reactivated quickly,” said Olivier Schwartz. However, the protection of cellular immunity varies according to the age of the individual. “For older and immunocompromised people, the immune system reacts less well to vaccination and, probably, the duration of this protection will be shorter”, continues Yannick Simonin. Among the vaccination schemes envisaged, we could therefore move, in the future, towards an annual or biannual booster for the fringe of the population most at risk. The objective: to stimulate the humoral and cellular response so that it remains robust over time.