Question asked by 05/19/2020
Hello,
Your question refers to several studies published in May, which refer to the principle of immune memory, the principle of which can be recalled in a few words.
On the surface and at the heart of viruses are molecules that will react with the human immune system, triggering a number of defense mechanisms. These viral structures recognized by the body are called “antigens”.
Following an infection, cells specialized in the detection of these antigens (“memory” B and T lymphocytes) persist more or less durably in the organism. When re-exposed to the viral antigen, these cells allow a faster immune response (including the production of antibodies by B cells). This “immune memory” can durably protect against the occurrence of new infections. For example, it is thanks to this mechanism that it is extremely rare for a person to contract chickenpox twice.
Are there cases of cross-immunity between different coronaviruses?
In order for a virus to wake up the immune memory, it must therefore have one or more antigens on its surface capable of causing “memory” lymphocytes to react.
The Sars-CoV-2 virus, responsible for Covid-19, is a new pathogen to which humans have never been massively exposed before. However, it belongs to the vast family of coronaviruses, seven of which can infect humans. Four are responsible, in our species, for essentially benign seasonal diseases (colds): alphacoronaviruses 229E, NL63 and betacoronaviruses OC43 and HKU1.
Since the appearance of Sars-CoV-2 (a betacoronavirus), many researchers have wondered if some of its antigens would not have enough homologies with those present on the surface of other coronaviruses, to significantly react a previous immune memory.
In fact, some studies carried out over the past fifteen years have shown that betacoronaviruses can induce immune responses against other viruses of the same family. It has been shown that people infected with OC43 have antibodies capable of recognizing the virus responsible for the 2002 SARS epidemic (Sars-CoV-1, which circulated little outside of China). Symmetrically, infection with Sars-CoV-1 can lead to the production of antibodies reactive to OC43.
However, such crossover immune reactions are far from systematic. Thus, in 2015, a study on a patient positive for the Mers coronavirus had shown that his memory lymphocytes did not react to the specific antigens of Sars-CoV-1.
Since the start of the Covid-19 epidemic, the hypothesis of cross-immunity has therefore been considered with great caution. However, in early March, experiments on mice suggested that antibodies reactive to the Sars-CoV-1 antigens could interact with those of Sars-CoV-2. If other research conducted in vitro, published in Science and Nature, have suggested that such a cross reaction exists in humans, this track turns out ultimately inconclusive.
In an experiment described in early June in Cell Reports, eleven blood samples from Covid + patients were exposed to the Sars-CoV-1 virus. An association reaction with antibodies was observed in only one of the samples, and at an intensity deemed too low to be able to confer, on an organism-wide basis, real protection against infection. The researchers also noted the lack of reaction by exposing Sars-CoV-2 to blood samples from 2002 SARS survivors.
What about other betacoronaviruses?
Research published in mid-May has brought the hypothesis of cross-immunity to other betacoronaviruses back to the fore. The most notable works on this subject were presented on May 14 in the journal Cell. The initial objective of this study was to measure the presence of two types of T lymphocytes in 20 patients cured of Sars-CoV-2, in order to assess the existence of acquired immunity to the virus. The researchers also performed this measurement on samples taken from 20 patients who had never been exposed to Covid-19. Surprisingly, almost half of the control group had CD4 lymphocytes reacting to certain Sars-CoV-2 antigens used for the tests.
However, this laboratory reaction does not at all prove that the immune response of these naive people to Sars-CoV-2 would be strong enough to prevent infection. It turns out, moreover, that the people in the “control” group who did not react to the antigens of Sars-CoV-2 … nevertheless all had antibodies against other “benign” coronaviruses. In other words: the presence of antibodies from exposure to other coronaviruses does not necessarily imply an immune response in the presence of Sars-CoV-2. It should be noted that these various results appear consistent with those of other works, pre-published in late April by a German team and in mid-May by a British team.
Another signal presented as favorable to the hypothesis of cross immunity comes from work on animals, published on May 20 in the journal Science. This is a vaccine trial, carried out on 25 rhesus macaques. Before injecting the Sars-CoV-2 vaccine candidate into animals, the researchers performed a measurement of their antibodies. In two macaques, they found the presence of antibodies that reacted to the presence of a Sars-CoV-2 antigen used in the vaccine. However, none of the animals had been exposed to this coronavirus. This result suggests that 2 of the 25 macaques had previously been exposed to a virus carrying a neighboring antigen, and therefore that a “crossed” immune reaction is possible. However, the coronaviruses that can infect rhesus macaques are not necessarily the same to which humans are commonly exposed.
A final element suggests that previous exposure to benign coronaviruses is insufficient to protect against infection: the rate of infection observed in very confined environments. For example, it has been established that at least two-thirds of the crew of the aircraft carrier Charles-de-Gaulle were infected with the Sars-CoV-2, as were 100% of those present in a long-term care center in a Quebec city. However, in the general population, it is estimated that more than 90% of adults have antibodies against three of the main human coronaviruses.
These data suggest that a hypothetical “cross-immunity” would only have a protective effect at best in a small proportion of the population.
On May 27, invited to comment on recent experimental results suggesting the possibility of cross-immunity, Michael Ryan – executive director of the WHO program for the management of health emergencies – made it clear that there is no was currently “No empirical evidence that previous infections with coronaviruses protect against infections by [Sars-CoV-2]”
The existence of partial cross-immunity may affect the effectiveness of the vaccine
On the other hand, if the existence of sufficiently strong immune cross-reactions with other coronaviruses would make it possible to more easily contain the pandemic, an incomplete “cross-immune” immune reaction could have a deleterious effect … on the effectiveness of a future vaccine.
As recalled by our colleague Stéphane Korsia-Meffre in a very complete article published on the site of Vidal, this phenomenon has already been observed with influenza vaccines. Indeed, a vaccine against Covid-19 will probably use antigenic fragments of Sars-CoV-2 (to elicit a specific response, and to generate an immune memory). However, if the selected Sars-CoV-2 fragments are not sufficiently characteristic, and even prove to be too similar to those of other betacoronaviruses, they could be destroyed by the antibodies already present. And this, without having had time to generate the specific immune response which, alone, can prepare for a real subsequent infection.
In summary
In the current state of knowledge, the fact of having contracted certain diseases in the past does not ensure, in humans, sufficient protection against Sars-CoV-2. And observing an immune activity in the laboratory does not make it possible to know if it is sufficient to protect from an infection.
Florian Gouthière
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