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Cellular immune responses to covid-19

Authors:
Herb Sewell at University of Nottingham
Herb Sewell
Raymond Martin Agius at The University of Manchester
Raymond Martin Agius
Marcia Stewart
Marcia Stewart
Denise Kendrick
Denise Kendrick
Denise Kendrick
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Cellular immune responses to covid-19
T cells could be valuable allies in pandemic control
Herb F Sewell, 1Raymond M Agius, 2Marcia Stewart, 3Denise Kendrick1
Protective and enduring immune responses to viral
infections or vaccines usually arise from the
combined actions of lymphocytes: B cells (responsible
for humoral antibody immunity) and T cells
(responsible for cellular immunity and helping B cell
responses).
B cells produce detectable antibodies in classes IgM,
IgG, and IgA along with lesser amounts of IgD and
IgE. For SARS-CoV-2, the causative agent of covid-19,
the focus is mainly on IgM, IgG, and IgA antibodies
that can neutralise the virus by binding to the spike
and other membrane proteins and thus preventing
infection.1Understanding the lesser known roles of
T cells and cellular immunity will deepen our insights
into covid-19 pathogenesis and help inform both
vaccine development and pandemic containment
strategies.
An effective immune response to SARS-CoV-2 involves
four types or subsets of T cells: T helper cells (CD4)
are responsible for cellular immunity and for helping
B cells to produce neutralising antibodies; cytotoxic
or killer T cells (CD8) directly kill infected cells—aided
by helper T cells2; other T cells (including T-17 (Th17)
cells) drive the inflammatory responses that help to
control infections3; and regulatory T cells (T regs)
help to contain the immune response, to prevent
over-reaction and damage to tissues.
CD4 T cells ensure all these components work
together by secreting small short acting cytokines
that bind to receptors on target cells. Importantly, all
B and T cell types have immunological memory after
a first encounter with a pathogen. This enables a
faster effective response after a second encounter
with the same pathogen or one that is closely related
(cross reaction).
Preliminary studies from the US and Europe recently
documented T cells specific to SARS-CoV-2 in people
with acute covid-19 and in those recovering from
infection.4 -6 They report helper and killer T cells
specific to SARS-CoV-2 in people with and without
antibodies.6More unexpectedly, they found specific
T cells in people with no history of exposure to
SARS-CoV-2—individuals who had repeatedly
swabbed negative for the virus.4These cells have
even been found in stored blood taken before the
pandemic (2015-18). Finally, the studies identified
strong T cell memory responses in people recovering
from covid-19. Memory cells are critical for protective
and enduring immunity.
What are the implications of these early findings?
Principally, these studies show that a good T cell
immune response and immunological memory
accompany natural exposure to or infection with
SARS-CoV-2, that evidence of these responses is
present in some people who have apparently never
encountered the virus, and that T cell immune
responses can exist in the absence of detectable
antibodies.
Collectively, these features suggest that candidate
vaccines7should aim to stimulate both B cell
(neutralising) antibodies and T cell antiviral
responses.8Early phase clinical trials of candidate
vaccines developed in Oxford, UK, and in China do
show concomitant B cell neutralising antibodies and
antiviral T cells in vaccinated healthy volunteers,9 10
improving prospects for protective immunity. This
combined response is a feature of many successful
vaccines, including vaccines against varicella
(chickenpox), influenza, measles, and hepatitis B.
Immune memory
That some “virus naive”participants in early studies
had pre-existing memory helper (50% of participants)
and killer T (20%) cells with potential activity against
SARS-CoV-2 is intriguing. These cells might arise from
cross reactions to other circulating coronaviruses,
such as some common cold viruses, and might be a
welcome hint of possible background immunity to
covid-19 in populations at risk—even in the absence
of antibodies.
Any cellular immune memory for SARS-CoV-2 in the
population could enhance responses to vaccines and
might also give a vaccination programme a head start
towards herd immunity. Herd immunity is population
resistance to spread of an infection, achieved when
a high enough proportion of individuals are immune,
usually through vaccination.11 12
Pre-existing memory helper T cells specific to
SARS-CoV-2 could boost the production of
neutralising IgG antibodies in the blood of newly
exposed people and could also enhance antibody
protection at mucosal surfaces through IgA in saliva,
tears, or nasal secretions.13 -15 Such IgA antibodies
act as a protective barrier at common viral entry
points. Research is now required to further
characterise these possible immune pathways
including memory B and T cells in mucosal tissues.
Research should also explore the role of regulatory
T cells in severe covid-19, particularly cytokine storm
syndrome16 and the documented association between
high titres of IgG antibodies and poorer disease
outcomes including death.17 Both might reflect
ineffective control of inflammation by regulatory T
cells.
Recent findings on the role of T cells in covid-19 give
us cause to be cautiously optimistic that cellular
immune responses could be a valuable ally in global
efforts to control this and future pandemics.
1the bmj | BMJ 2020;370:m3018 | doi: 10.1136/bmj.m3018
EDITORIALS
1University of Nottingham,
Nottingham, UK
2University of Manchester,
Manchester, UK
3De Montfort University, Leicester, UK
Correspondence to: H Sewell
herb.sewell@nottingham.ac.uk
Cite this as:
BMJ
2020;370:m3018
http://dx.doi.org/10.1136/bmj.m3018
Published: 31 July 2020
on 26 September 2020 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.m3018 on 31 July 2020. Downloaded from
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial
companies. The authors declare the following other interests: None
Provenance and peer review: Commissioned, not peer reviewed
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the bmj | BMJ 2020;370:m3018 | doi: 10.1136/bmj.m30182
EDITORIALS
on 26 September 2020 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.m3018 on 31 July 2020. Downloaded from
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Full-text available
  • Jul 2020
Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10¹⁰ viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R²=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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A mathematical model reveals the influence of population heterogeneity on herd immunity to SARS-CoV-2
Article
Full-text available
  • Jun 2020
  • SCIENCE
Heterogeneity and herd immunity In response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some politicians have been keen to exploit the idea of achieving herd immunity. Countering this possibility are estimates derived from work on historical vaccination studies, which suggest that herd immunity may only be achieved at an unacceptable cost of lives. Because human populations are far from homogeneous, Britton et al. show that by introducing age and activity heterogeneities into population models for SARS-CoV-2, herd immunity can be achieved at a population-wide infection rate of ∼40%, considerably lower than previous estimates. This shift is because transmission and immunity are concentrated among the most active members of a population, who are often younger and less vulnerable. If nonpharmaceutical interventions are very strict, no herd immunity is achieved, and infections will then resurge if they are eased too quickly. Science , this issue p. 846
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Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals
Article
Full-text available
  • May 2020
  • CELL
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8⁺ and CD4⁺ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4⁺ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4⁺ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8⁺ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4⁺ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.
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Imbalanced host response to SARS-CoV-2 drives development of COVID-19
Article
Full-text available
  • Apr 2020
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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Antibody Responses to SARS-CoV-2 in Patients With Novel Coronavirus Disease 2019
Article
Full-text available
  • Mar 2020
  • CLIN INFECT DIS
Background: The novel coronavirus SARS-CoV-2 is a newly emerging virus. The antibody response in infected patient remains largely unknown, and the clinical values of antibody testing have not been fully demonstrated. Methods: A total of 173 patients with SARS-CoV-2 infection were enrolled. Their serial plasma samples (n=535) collected during the hospitalization were tested for total antibodies (Ab), IgM and IgG against SARS-CoV-2. The dynamics of antibodies with the disease progress was analyzed. Results: Among 173 patients, the seroconversion rate for Ab, IgM and IgG was 93.1%, 82.7% and 64.7%, respectively. The reason for the negative antibody findings in 12 patients might due to the lack of blood samples at the later stage of illness. The median seroconversion time for Ab, IgM and then IgG were day-11, day-12 and day-14, separately. The presence of antibodies was <40% among patients within 1-week since onset, and rapidly increased to 100.0% (Ab), 94.3% (IgM) and 79.8% (IgG) since day-15 after onset. In contrast, RNA detectability decreased from 66.7% (58/87) in samples collected before day-7 to 45.5% (25/55) during day 15-39. Combining RNA and antibody detections significantly improved the sensitivity of pathogenic diagnosis for COVID-19 (p<0.001), even in early phase of 1-week since onset (p=0.007). Moreover, a higher titer of Ab was independently associated with a worse clinical classification (p=0.006). Conclusions: The antibody detection offers vital clinical information during the course of SARS-CoV-2 infection. The findings provide strong empirical support for the routine application of serological testing in the diagnosis and management of COVID-19 patients.
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CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities
Article
Full-text available
  • Dec 2019
CD4⁺ T cell help is required for the generation of CD8⁺ cytotoxic T lymphocyte (CTL) memory. Here, we use genome-wide analyses to show how CD4⁺ T cell help delivered during priming promotes memory differentiation of CTLs. Help signals enhance IL-15-dependent maintenance of central memory T (TCM) cells. More importantly, help signals regulate the size and function of the effector memory T (TEM) cell pool. Helped TEM cells produce Granzyme B and IFNγ upon antigen-independent, innate-like recall by IL-12 and IL-18. In addition, helped memory CTLs express the effector program characteristic of helped primary CTLs upon recall with MHC class I-restricted antigens, likely due to epigenetic imprinting and sustained mRNA expression of effector genes. Our data thus indicate that during priming, CD4⁺ T cell help optimizes CTL memory by creating TEM cells with innate and help-independent antigen-specific recall capacities.
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Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial
Article
  • Jul 2020
Background This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. Methods This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 10¹¹ viral particles per mL or 5 × 10¹⁰ viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. Findings 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 10¹¹ viral particles n=253; 5 × 10¹⁰ viral particles n=129) or placebo (n=126). In the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 10¹¹ and 5 × 10¹⁰ viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 10¹¹ viral particles dose group and one (1%) participant in the 5 × 10¹⁰ viral particles dose group. No serious adverse reactions were documented. Interpretation The Ad5-vectored COVID-19 vaccine at 5 × 10¹⁰ viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. Funding National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
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Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
Article
  • Mar 2020
  • CELL
The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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