T-cell responses may help predict protection against SARS-CoV-
2 infection in individuals with and without cancer
Results may inform future COVID-19 vaccine development

Date:
February 18, 2022
Source:
American Association for Cancer Research
Summary:
T-cell responses directed against the receptor-binding domain of
the SARS-CoV-2 spike protein were associated with protection from
SARS-CoV- 2 infection in vaccinated individuals with or without
cancer, with lower T-cell responses observed in patients with
blood cancers, according to a new study.



FULL STORY ========================================================================== T-cell responses directed against the receptor-binding domain of the
SARS-CoV- 2 spike protein were associated with protection from SARS-CoV-2 infection in vaccinated individuals with or without cancer, with lower
T-cell responses observed in patients with blood cancers, according to
results from a study published in Cancer Discovery, a journal of the
American Association for Cancer Research.


==========================================================================
The efficacy of COVID-19 vaccines has been typically measured by
antibody levels, but this may not be a reliable metric, explained
Laurence Zitvogel, MD, PhD, a professor at the Gustave Roussy Institute in Villejuif, France. "Humoral immune responses monitored by antibody titers
are only transiently helpful and not well correlated with protection,"
she said. "Antibodies do not last more than a couple of weeks in a
given individual post-infection or post- vaccination. Data show that
antibodies against the SARS-CoV-2 spike protein have failed to predict
actual protection against reinfection or breakthrough infection."
Measuring antibody levels is a way to monitor the presence and the
activity of memory B cells, which are immune cells that produce antibodies
and represent the first arm of adaptive immunity. T cells, another type
of immune cell, represent the second arm of long-term immunity and can
be amplified during infection to kill infected cells directly.

In this study, Zitvogel and colleagues examined whether T-cell responses
could be a reliable indicator of protection against SARS-CoV-2 infection
in healthy individuals and in patients with cancer who had not been
exposed to the virus during the first wave of the pandemic. Using blood
samples collected prior to infection with SARS-CoV-2, they performed
various in vitro experiments to assess how the polarity and repertoire
of T-cell responses correlated with susceptibility to infection with
SARS-CoV-2 during subsequent waves of the pandemic.

T-cell polarity was assessed by identifying the types of cytokines --
which are immune-stimulating proteins -- released by the T cells of
each individual when exposed to a viral antigen. The release of the IL-2 cytokine was indicative of Th1 T cells, whereas the release of the IL-5 cytokine indicated Th2 T cells.

Zitvogel and colleagues examined the makeup of each individual's T-cell
pool to determine the proportion of Th1 and Th2 T cells.

They found pre-existing SARS-CoV-2-specific T cell responses in about
20-25 percent of the population, both in healthy individuals and in
cancer patients.

In addition, they observed that the types of cytokines released by memory
T cells were associated with protection against SARS-CoV-2 infection. An imbalance between the IL-2 and IL-5 cytokines was associated with a higher susceptibility to SARS-CoV-2 infection, with an IL-2/IL-5 ratio less
than 1 predicting infection, regardless of cancer status. This suggests
that the relative levels of cytokines released by T cells may provide
insight into susceptibility to SARS-CoV-2 infection, explained Zitvogel.



========================================================================== Further analysis revealed that T cells from individuals who had
developed a primary infection, breakthrough infection post-vaccination,
or reinfection with SARS-CoV-2 did not react to the receptor-binding
domain of the spike protein, despite having immune responses against
other regions of the viral genome.

Zitvogel and colleagues proposed that the lack of reactivity to the spike receptor-binding domain may have made these individuals more susceptible
to infection. Additionally, Zitvogel proposed that T-cell reactivity
to the receptor-binding domain could even drive evolution of the spike
protein, potentially contributing to the emergence of new viral variants.

Zitvogel and colleagues also examined post-vaccination T-cell responses
in healthy individuals and in patients with solid or blood cancers. They
found that post-vaccination T-cell responses varied among these
populations, with patients with blood cancers having significantly lower responses than patients with solid tumors and cancer-free individuals. Ten percent of patients with blood cancers had T cells that were reactive to
the receptor-binding domain of the spike protein, compared with 49 percent
of cancer-free individuals and 34 percent of patients with solid tumors.

The researchers observed that vaccine-induced T-cell responses against
the original, wild-type sequence of the spike receptor-binding domain
were poorly cross-reactive against the receptor-binding domain of the
alpha, beta, and delta viral variants. "This may explain why the omicron variant of SARS-CoV- 2 is currently spreading among the vaccinees," said Zitvogel. "The available vaccines were developed against the original
sequence of the receptor-binding domain and not against the mutated
sequences found in the variants." Together, the results of this study
indicate that both the polarity and the specificity of T-cell immune
responses may be involved in protection against SARS-CoV-2 infection,
concluded Zitvogel. "Our data suggest that there should be a greater
focus on monitoring long-term T-cell responses rather than antibody
titers, which are only reliable for a short time after vaccination." Furthermore, Zitvogel noted that antibody titers and T-cell responses
against the spike receptor-binding domain from current and emerging
variants of concern should be monitored, rather than those against
the original strain of the virus. Given the low T-cell responses after vaccination in patients with blood cancers, Zitvogel added that booster vaccinations should be strongly encouraged for these patients.

In addition, she noted that the results of this study could inform
vaccine development against emerging variants of SARS-CoV-2. "For the
greatest efficacy, the next generation of vaccines should elicit T-cell responses against the receptor-binding domain of the spike protein of
emerging viral variants," Zitvogel said.

A limitation of the study is that it only examined immune responses from
blood and may have missed potential impacts of mucosal immunity. An
additional limitation is that researchers did not measure T-cell
responses against non- structural viral proteins. Third, researchers
employed cross-sectional comparisons among various patient categories
instead of conducting a longitudinal paired follow-up after vaccination.

The study was supported by the Gustave Roussy Foundation; the French
Ministry of Education, Research and Innovation; BioMe'rieux, Transgene, Malakoff Humanis, and the Prism Project through a grant from the Agence Nationale de la Recherche. Zitvogel is a cofounder of EverImmune.

========================================================================== Story Source: Materials provided by
American_Association_for_Cancer_Research. Note: Content may be edited
for style and length.


==========================================================================


Link to news story: https://www.sciencedaily.com/releases/2022/02/220218080249.htm

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