Cell-mediated immunity is essential to prevent reinfection by the novel coronavirus, study suggests

Brazilian researchers studied the case of identical twins in which only one sibling was reinfected and developed complications after a second exposure to the virus. Their analysis showed that the adaptive immune response can be different even between individuals with the same genome.

By Maria Fernanda Ziegler  |  Agência FAPESP – In Brazil, two young women who are identical twins living in the same house contracted COVID-19 and had mild symptoms, such as a fever, cough and nasal congestion, with no need for hospitalization. Four months later, in August 2020, one of the twins (a healthcare worker) was reinfected, but this time her condition became worse, with low blood oxygen levels, and she was hospitalized for ten days, partly in intensive care. Her sister was not reinfected despite this renewed exposure to the virus.

Despite the appearance of an unusual chance event, among so many reported during the pandemic, researchers at the University of São Paulo (USP) took the opportunity to investigate cases of reinfection in subjects with the same genome. Their findings highlight the key role played by cellular immunity, the adaptive immune response specific to each pathogen and mediated by T cells, in avoidance of reinfection.

“Identical twins would be expected to display similar symptoms. Nevertheless, we identified a case in which the results were very different. Only one sibling had COVID-19 a second time and was found to have an immune response that was lacking in specific T cells. In the study, we observed that monozygotic twins [resulting from the fertilization of a single egg that splits in two] can have different adaptive immune responses,” said Mayana Zatz, a professor at the University of São Paulo’s Institute of Biosciences (IB-USP) and principal investigator for the Human Genome and Stem-Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.

The discovery relating to the role of T cells in preventing reinfection was made during a broader research project on the immune system with the participation of identical twins. The study was supported by FAPESP and reported in an article posted to the preprint platform medRxiv but not yet peer-reviewed.

Lines of defense

The immune system comprises several lines of defense, including physical and chemical barriers, non-specific innate responses, and specific adaptive responses. As noted in the article, the first line of defense against viruses is the release of cytokines by the innate system. T cells are a major part of the adaptive response, alongside antibody-producing B cells. Also called T lymphocytes, their roles include directly killing infected host cells.

When a virus infects a person and begins multiplying in their cells, it first triggers an innate immune response, which is non-specific. Interferons and other cytokines act as a sort of padlock, preventing infected cells from replicating the virus and summoning macrophages to engulf and destroy them.

If the innate immune system fails to solve the problem, enter the adaptive immune system, which includes neutralizing antibodies (humoral response), and T cells (cell-mediated response), which eliminate pathogens and infected cells.

To find out why the response was different in each twin, the researchers conducted a comprehensive assessment of their innate immune system, involving an investigation of type I and III interferon production, and of their acquired immunity, including production of neutralizing antibodies and the response of T cells to synthesized viral peptides.

“Our analysis of blood samples from the twins showed similar levels of type I and III interferons and neutralizing antibodies. The reinfected sibling had a higher level of antibodies because reinfection was recent, but there was a huge difference in the T cell-mediated immune response,” said Edecio Cunha Neto, last author of the article. Cunha Neto is a professor in the Department of Clinical Medicine at the Heart Institute (INCOR) of the University of São Paulo’s Medical School (FM-USP).

To deepen the analysis, the researchers compared the results of the tests on blood samples from the twins with those from another pair of identical twins who had asymptomatic COVID-19 a single time and served as a control group.

Of the 46 peptides or fragments of SARS-CoV-2 that are most easily recognized by T cells, blood cells from the reinfected sibling recognized only seven (15%), whereas cells from her twin sister recognized 40 (87%). There was a difference between the other two twins in the control group, but both recognized almost 100%.

“Our findings reinforce the theory that the immune repertory is defined somatically [by mutations occurring at more advanced stages of development] and that random individual responses are produced independently of the genetic framework, justifying distinct profiles observed in monozygotic twins. In other words, the immune repertory is developed out of successive exposures to pathogens, environmental stimuli and genetic factors that together configure a unique immune response in each individual,” said Mateus Vidigal de Castro, first author of the article and a postdoctoral researcher at IB-USP.

Recurrence of COVID-19 is poorly understood. Before the novel variants of SARS-CoV-2 emerged, it was thought to happen to one in 1,000 people. Discordant twin reinfection is even less frequent.  “In cases of recurrence, we would expect the immune response to the second infection to be stronger because of immune memory and specificity. However, the reinfected twin’s T cell response was weak, unlike her sister’s,” Cunha Neto said. “This disparity between subjects with the same genome shows that not only antibodies are extremely important in the response to COVID-19.”

Zatz said the analysis of discordant twins offers pointers for future research on immunity and COVID-19. “What’s most interesting is that the case reveals important clues to the complexity of the immune system and COVID-19 for the population in general,” she noted.

Vaccines and viral variants

The study also serves to reaffirm the idea that vaccines are most effective when they are strongly immunogenic, activating all the different cells and proteins in the immune system. In the case of the discordant twins, both infection and reinfection occurred last year, when the more transmissible variants had not yet appeared. Nevertheless, the researchers stressed the importance of T cells to protection against novel viral variants.

“There’s a lot of concern that novel variants of SARS-CoV-2 may be able to evade the neutralizing antibodies induced by both vaccination and prior infection. Our study emphasizes the importance of cell-mediated immunity to protect against recurrence and reinfection for the overall population,” Cunha Neto said.

Recent research has shown that the immune response mediated by T cells is less affected by novel viral variants than the humoral response. “This suggests the protection conferred by the cell-mediated response induced by the original virus or by vaccination may be effective against novel variants,” he stressed.

The article “Monozygotic twins discordant for severe clinical recurrence of COVID-19 show drastically distinct T cell responses to SARS-CoV-2” is at: www.medrxiv.org/content/10.1101/2021.03.26.21253645v1.