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Review

The Influence of Cross-Reactive T Cells in COVID-19

by
Peter J. Eggenhuizen
* and
Joshua D. Ooi
Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3800, Australia
*
Author to whom correspondence should be addressed.
Biomedicines 2024, 12(3), 564; https://doi.org/10.3390/biomedicines12030564
Submission received: 28 January 2024 / Revised: 28 February 2024 / Accepted: 1 March 2024 / Published: 2 March 2024
(This article belongs to the Section Molecular and Translational Medicine)
Browse Figure
Review Reports Versions Notes

Abstract

:
Memory T cells form from the adaptive immune response to historic infections or vaccinations. Some memory T cells have the potential to recognise unrelated pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and generate cross-reactive immune responses. Notably, such T cell cross-reactivity has been observed between SARS-CoV-2 and other human coronaviruses. T cell cross-reactivity has also been observed between SARS-CoV-2 variants from unrelated microbes and unrelated vaccinations against influenza A, tuberculosis and measles, mumps and rubella. Extensive research and debate is underway to understand the mechanism and role of T cell cross-reactivity and how it relates to Coronavirus disease 2019 (COVID-19) outcomes. Here, we review the evidence for the ability of pre-existing memory T cells to cross-react with SARS-CoV-2. We discuss the latest findings on the impact of T cell cross-reactivity and the extent to which it can cross-protect from COVID-19.

1. Introduction: SARS-CoV-2 and COVID-19

The Betacoronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and is responsible for the recent human pandemic [1,2]. Upon infection, the human immune system mounts an orchestrated response to contain the viral load, which initiates with the innate immune system by producing type I interferons [3,4] that are crucial in mounting a functional and effective initial response [5] and sets the premise for a successful adaptive immune response and a favourable clinical outcome [6].

2. Adaptive Immune Response to SARS-CoV-2

T cells form part of the adaptive immune response, and they are crucial to combat SARS-CoV-2 infection since convalescent individuals exhibit SARS-CoV-2-specific T cell memory [7]. The early involvement of CD8+ cytotoxic T cells around 7–14 days after symptom onset are critical for effectively clearing the virus, resulting in mild symptoms [8,9], and these follow a similar timeline to the humoral response [10]. Immune dysregulation during SARS-CoV-2 infection leads to poorer prognosis. Ineffective interferon signalling during acute infection and T cell dysfunction, T cell number imbalance and CD8+ lymphopenia result in more severe COVID-19 clinical outcomes [11,12]. The cellular immune response, inclusive of antigen-specific and bystander effects, is also critical for driving disease outcomes, where a type 1 CD4+ T cell phenotype is associated with viral control, less-severe disease and clearance, whereas a type 2 CD4+ T cell phenotype is associated with more severe disease outcomes [8,13,14].
The adaptive immune response to SARS-CoV-2 is antigen-specific in nature through the processing and presentation of SARS-CoV-2 epitopes bound to major histocompatibility complex (MHC) on antigen presenting cells; CD8+ T cells through their T cell receptor (TCR) recognise SARS-CoV-2 antigens presented by MHC class I and CD4+ T cells through their TCR-recognising SARS-CoV-2 antigens presented by the MHC class II. The SARS-CoV-2 epitopes responsible for driving the adaptive immune response have been studied in great detail since the SARS-CoV-2 sequence was released [12,15,16]. Antigen-specific responses have been identified across all SARS-CoV-2 proteins by both CD4+ and CD8+ T cells, and over two thousand epitopes have been identified to date [17,18,19]. The immunodominant regions of SARS-CoV-2 responsible for the majority of immune responses have been extensively studied, including those commonly shared between different HLA-typed donors [15,20]. Responses to spike antigens are both CD4+ and CD8+ T cell-dominated, with the SARS-CoV-2-specific CD4+ T cells and T follicular helper cells assisting in the production of antibodies [15,16,17,21,22,23]. Notable non-spike CD8+ T cell responses protecting from severe COVID-19 include SARS-CoV-2 nucleocapsid protein [24,25]. Other non-spike epitopes recognised by T cells are derived from the membrane protein and non-structural proteins (NSPs) [15,16,26,27,28]. Overall, individuals typically show expanded epitope-specific responses to between 17 and 19 different SARS-CoV-2 epitopes, forming approximately 0.5% of the total CD4+ T cell repertoire and 0.2% of the total CD8+ T cell repertoire [15,27]. After infection, SARS-CoV-2-specific T cells become memory T cells, which are predominately CD4+ and exhibit a central memory phenotype and T effector memory re-expressing CD45RA (TEMRA) cells [27,29,30,31]. To date, this memory pool is robust, with a half-life of approximately 200 days pointing to a slow decrease in frequency over time [27,32].
Although cellular immunity to SARS-CoV-2 predominantly arises from SARS-CoV-2-specific T cells via SARS-CoV-2 infection or vaccination, there is a growing appreciation of the contribution of antigen-specific T cell responses arising from pre-existing memory T cells from infections or vaccinations other than SARS-CoV-2 [16,33,34,35,36]. Such T cell cross-reactivity can arise through T cell receptor (TCR)-dependent mechanisms [37,38,39].

3. TCR-Dependent Cross-Reactivity

TCR-dependent cross-reactivity arises through T cell cross-reactivity between unrelated pathogens via TCRs that can recognise both pathogens. Initially, an infection or immunisation produces memory T cells that, upon exposure to a second, different infection, cross-react and activate the memory T cells to become effector T cells (Figure 1) [40]. This happens via a TCR on the memory T cell that can sufficiently bind to MHC, presenting either the epitope from the first pathogen or the similar epitope from the second pathogen. The mechanisms behind TCR-dependent T cell cross-reactivity are actively being explored in COVID-19, as well as any correlate of protection they may have in improving COVID-19 outcomes. This review will cover three aspects of T cell cross-reactivity to SARS-CoV-2: (1) T cell cross-reactivity and cross-protection between SARS-CoV-2 and other human coronaviruses. (2) The cross-reactive T cell response to novel SARS-CoV-2 variants in the context of pre-existing SARS-CoV-2 T cell immunity from SARS-CoV-2 vaccination or prior infection. (3) Cross-reactive T cell responses from other pathogens and vaccines, such as the influenza, measles, mumps and rubella (MMR) and Bacillus Calmette–Guérin (BCG) vaccines.
Cross-reactive T cells first arise when naïve T cells recognise, through their T cell receptor (TCR), an antigen from the vaccine or pathogen presented by the major histocompatibility complex (MHC) on antigen-presenting cells (APC) such as dendritic cells (DC). These T cells become T effectors before contracting into a T memory (T mem) phenotype. Given sufficient structural or sequence similarity between the first antigen and SARS-CoV-2, the TCR on the memory T cell can recognise the SARS-CoV-2 antigen presented by DC/APC. This activates the T cell to become a T effector and produce cross-reactive T cell responses.

4. T cell Cross-Reactivity between SARS-CoV-2 and Other Human Coronaviruses

Cross-reactive T cells between SARS-CoV-2 and other human coronaviruses (HCoVs) were identified early on in the pandemic in individuals unexposed to SARS-CoV-2 [16,33,34,41,42,43,44]. The less serious, seasonal HCoVs are the Betacoronavirus OC43 and HKU1 and Alphacoronavirus NL63 and 229E. Approximately 90% of the adult human population has been exposed to each of these viruses, and the four seasonal coronaviruses are responsible for 15–30% of all respiratory tract infections each year, meaning there is a great deal of potential for the pool of memory T cells to cross-react with SARS-CoV-2 [45,46]. Other more serious but less common HCoVs are Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1. These six HCoVs share a degree of amino acid sequence homology with SARS-CoV-2 and, thus, contribute to T cell cross-reactive responses.
The seasonal HCoVs, although prevalent, do not sustain antibodies long-term, and T cell memory responses are present but generally of low magnitude, meaning humans can typically become reinfected within 12 months [47,48]. For SARS-CoV-1, responsible for the 2002–2004 SARS outbreak, memory T cell responses were detectable as long as 17 years after infection, much longer than humoral responses [33]. For MERS-CoV, a similar persistence of T cell responses over humoral responses was observed [49,50,51]. Overall, this highlights the importance of T cell memory and its potential for cross-reactivity among shared epitopes in controlling genetics-related HcoV infections, such as SARS-CoV-2.
SARS-CoV-2-specific T cells have been identified in unexposed individuals, and they are suspected to arise from memory T cell cross-reactivity from previous HcoV infections, which share key T cell epitopes [16,33,34,41,42,43,44,52,53]. A list of SARS-CoV-2 T cell epitopes shown to cross-react with other human coronaviruses is found in Table 1. Cross-reactive T cell responses have been shown to generate functional T cell responses in most but not all reports [12,33,52,54]. However, there remains debate about whether the functionality of these cross-reactive T cells can contribute to the cross-protective effect and impact clinical outcomes.
There is evidence to suggest cross-reactive T cell immunity may not always correlate with positive clinical outcomes. It has been shown that cross-reactive T cells have a low avidity for SARS-CoV-2 homologues, and low avidity T cell responses are correlated with severe COVID-19 [55,56]. This suggests that TCR engagement with peptide-MHC may not be sufficient to properly activate the cross-reactive memory T cells and turn them into robust T effectors against SARS-CoV-2. Also, there is a risk that the cross-reactive T cell repertoire may actually hinder clinical outcomes by engaging only mildly effective effectors against the infection and occupy the immunological space at the expense of more effective, higher affinity/avidity TCR clonotypes [55].
Among adults, cross-reactive T cells against HcoVs are of a low magnitude, and their persistence is not fully understood [48]. Interestingly though, among young adults and children, cross-reactive T cells and antibodies are present, particularly against the spike 2 domain, a region that is relatively conserved between HcoVs [57,58]. Conversely, among the elderly, HcoV-specific T cells and antibodies are mostly non-existent [48]. This may be a contributing factor for why COVID-19 is relatively mild in children and more severe in the elderly.
Despite evidence showing that cross-reactive T cells are less effective in combatting SARS-CoV-2 infection, there is evidence to suggest that cross-reactive T cells can protect from severe COVID-19. In the context of previous recent HcoV infections, the HcoV-specific T cells are able to cross-react and protect against subsequent infection with SARS-CoV-2, which leads to less severe COVID-19 [59]. There may be a time-dependent effect for cross-protection by recent HcoV infection given that seasonal HcoV memory T cells are relatively short-lived. Another study associated protection from COVID-19 with cross-reactive T cells as higher frequencies of cross-reactive memory T cells against SARS-CoV-2 nucleocapsid were present in patients who remained PCR-negative despite exposure to SARS-CoV-2 compared to PCR-positive SARS-CoV-2-exposed individuals [60]. Thus, there is potential for cross-reactive T cells to result in asymptomatic COVID-19.
Another major contributor to HcoV cross-reactivity with SARS-CoV-2 arises from epitopes within the NSPs. Given that the NSPs are relatively well conserved between HcoVs and by harnessing the potential of cross-reactive T cell immunity, the shared homology between NSPs can be utilised for the development of a pan-coronavirus vaccine that has the potential to protect from seasonal HcoVs, SARS-CoV-2 and any future coronaviruses that may arise [61]. There has been much effort to define the cross-reactive epitopes and their associated TCRs that can recognise a broad range of HcoVs and even other zoonotic coronaviruses, which pose a risk to humans [25,56,62,63,64,65,66,67,68,69,70]. Pan-coronavirus vaccines are important for minimising the risk of further pandemics caused by coronaviruses. By utilizing cross-reactive T cell responses driven by non-spike epitopes such as NSPs, such an approach can protect from a variety of HcoVs as well as SARS-CoV-2.
The SARS-CoV-2 spike and nucleocapsid proteins are responsible for a major part of the natural adaptive immune response to SARS-CoV-2, with the spike notably being the antigen used in SARS-CoV-2 vaccines. T cell cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins has been implicated in cross-protective immunity. The spike and nucleocapsid epitopes of SARS-CoV-2 share significant homology with other HcoVs. In a humanised mouse model, prior infection with the HcoV OC43 protected mice against disease when infected with SARS-CoV-2. Cross-protection occurred due to CD4+ and CD8+ T cell cross-reactivity to key spike and nucleocapsid epitopes [71]. In humans, a common HLA type, HLA-B*15:01, has been shown to bind SARS-CoV-2 and multiple HcoV epitopes and produce cross-reactive memory T cell responses [72]. This immunodominant, the cross-reactive epitope is likely the reason for the strong association between individuals with HLA-B*15:01 and asymptomatic SARS-CoV-2 infection [73].
There are reports that SARS-CoV-1 and MERS-CoV memory T cells can cross-react with SARS-CoV-2, which is likely due to their close phylogenetic association and high sequence homology [33,74,75]. Both SARS-CoV-1 and MERS-CoV infections result in short-lived B cell and antibody responses but encouragingly long-lasting T cell memory responses up to 18 years post-infection [33,76,77]. However, upon closer inspection, there was low homology between the immunodominant SARS-CoV-2 epitopes and their homologues in SARS-CoV-1 [33,42,78,79]. This may mean that despite the high degree of homology between SARS-CoV-1, MERS-CoV and SARS-CoV-2, as well as the detectable and durable cross-reactive T cell responses already identified in multiple studies, the particular cross-reactive epitopes resulting in an effective immune response against SARS-CoV-2 are not covered by such cross-reactivity. As such, a cross-protective effect arising from such cross-reactivity may be insufficient, although the extent of any cross-protective effect in COVID-19 outcomes requires further research. Given that SARS-CoV-1 was a relatively isolated, historic outbreak from 2002 to 2004, the biological importance holds less relevance in terms of the current public health landscape.
Table 1. SARS-CoV-2 T cell epitopes known to cross-react with human coronavirus epitopes. This list is not exhaustive.
Table 1. SARS-CoV-2 T cell epitopes known to cross-react with human coronavirus epitopes. This list is not exhaustive.
HLA AssociationSARS-CoV-2 EpitopeSARS-CoV-2 SequenceReference
Cross-reactive Spike Epitopes
HLA-DPS355–364RKRISNCVAD[63]
HLA-DRS506–525QPYRVVVLSFELLHAPATVC[63]
NAS556–564NKKFLPFQQ[80]
NAS770–777IAVEQDKN[80]
NAS810–816KPSKRS[57]
NAS817–824FIEDLLFN[80]
HLA-DP S816–830SFIEDLLFNKVTLAD[42,44,56,63]
NAS851–856CAQKFN[57]
NAS901–906QMAYRF[57]
HLA-B*15:01S919–927NQKLIANQF[73]
HLA-A*02:01S976–984VLNDILSRL[81]
NAS997–1002ITGRLQ[57]
HLA-DPS981–1000LSRLDKVEAEVQIDRLITGR[63]
NAS1040–1044VDFCG[57]
NAS1148–1157FKEELDKYFK[80,82]
NAS1150–1156EELDKYF[80,82]
NAS1205–1212KYEQYIKW[57]
NAS1206–1220YEQYIKWPWYIWLGF[42]
HLA-A*24S1207–1215QYIKWPWYI[43]
Cross-reactive
NSP Epitopes
HLA-A*02:01NSP1
(ORF184–92)		VMVELVAEL[81]
HLA-A*01:01NSP3
(ORF11637–1646)		TTDPSFLGRY[43]
HLA-A*02:01NSP5
(ORF13467–3475)		VLAWLYAAV[81]
HLA-B*08NSP5
(ORF13361–3369)		TPKYKFVRI[43]
HLA-A*02:01NSP6
(ORF13690–3698)		KLKDCVMYA[83]
HLA-B*35NSP736–50HNDILLAKDTTEAFE[33]
NANSP726–40SKLWAQCVQLHNDIL[33]
HLA-A*02:01NSP8
(ORF14032–4040)		MLFTMLRKL[81]
NANSP8
(ORF13976–3990)		VLKKLKKSLNVAKSE[42]
HLA-B*08NSP10
(ORF14344–4352)		DLKGKYVQI[43]
NANSP12
(ORF15246–5260)		LMIERFVSLAIDAYP[42]
HLA-A*24NSP12
(ORF15137–5145)		FYAYLRKHF[83]
NANSP12
(ORF15136–5150)		EFYAYLRKHFSMMIL[42]
NANSP12
(ORF14966–4980)		KLLKSIAATRGATVV[42]
HLA-A*02:01NSP12
(ORF14515–4523)		TMADLVYAL[81]
NANSP13
(ORF15881–5895)		NVNRFNVAITRAKVG[42]
HLA-A*03NSP13
(ORF15455–5463)		KLFAAETLK[43]
NANSP13
(ORF15361–5375)		TSHKLVLSVNPYVCN[42]
HLA-B*40NSP14
(ORF16219–6228)		IEYPIIGDEL[43]
NANSP15
(ORF16751–6765)		LDDFVEIIKSQDLSV[43]
NAORF843–57SKWYIRVGARKSAPL[43]
NAORF7a90–104QEEVQELYSPIFLIV[43]
HLA-B*40ORF7a40–49YEGNSPFHPL[43]
HLA-DRORF626–40IWNLDYIINLIIKNL[43]
HLA-A*01ORF620–31RTFKVSIWNLDY[43]
Cross-reactive Nucleocapsid Epitopes
HLA-DRN50–64ASWFTALTQHGKEDL[43]
HLA-B*07N101–120MKDLSPRWYFYYLGTGPEAG[33,43]
HLA-B*07:01N105–113SPRWYFYYL[25,26,65,69,83]
HLA-DRN127–141KDGIIWVATEGALNT[43]
NAN221–235LLLLDRLNQLESKMS[43]
HLA-A*02:01N221–230LLLLDRLNQL[83]
HLA-DRN311–325ASAFFGMSRIGMEVT[43]
NAN326–340PSGTWLTYTGAIKLD[42]
NAN328–342GTWLTYTGAIKLDDK[43]
Instances where cross-reactive T cell immunity from HcoVs result in cross-protective effects in SARS-CoV-2 infection are now clearly established in the literature. Further research into the relative contribution of cross-protective versus de novo immunity in combatting COVID-19 would assist in unravelling the often-convoluted history of T cell memory mixed with the somewhat plastic nature of T cell cross-reactivity. In addition, further research is required to address the interplay between cross-reactive T cell immunity and other immune cells to mount an orchestrated immune response against SARS-CoV-2.

5. T Cell Cross-Reactivity between SARS-CoV-2 and Novel SARS-CoV-2 Variants

As the COVID-19 pandemic progressed, novel variants began to emerge that had the capacity to increase transmission or escape pre-existing immunity to prior SARS-CoV-2 infection or vaccination. These variants included Alpha, Beta, Gamma, Delta, Mu and Omicron, with Omicron having the highest number of mutations [84]. Some of these variants were in the receptor-binding domain of the spike protein, which is a key target for neutralizing antibodies and a target for SARS-CoV-2 vaccines. These variants were less able to be controlled by neutralizing antibodies, particularly the Omicron variant [85]. Despite the concerning decrease in humoral immunity to the novel variants, memory T cells remained largely unaffected. This is partly due to the majority of T cell epitopes in the variants remaining unchanged [66,86,87,88]. Some particular epitopes, in the context of certain HLA alleles, reported a decrease in memory T cell recognition by SARS-CoV-2 variants [89,90,91,92]. This highlights that in some populations, the cross-reactive T cell repertoire from previous SARS-CoV-2 exposure or vaccination may be less able to mount effective immune responses against novel variants. However, given the already characterised breath of memory T cell repertoire for SARS-CoV-2, there is less risk of immune escape [86,93]. The low risk of immune escape was corroborated, since, in the general population, approximately 80–100% T cell cross-reactivity between the original Wuhan strain of SARS-CoV-2 and later variants was observed [66,87,94,95,96,97,98]. The influence of cross-reactive T cells on SARS-CoV-2 variants contributed to protection from severe COVID-19 after re-infection, which remained high at over 88% protection against severe disease up to 40 weeks after the first infection regardless of the variant responsible for reinfection [99]. The preservation of cross-reactive memory T cell responses to SARS-CoV-2 variants of concern has ensured that prior SARS-CoV-2 exposure or vaccination can still have clinically protective effects upon exposure to novel SARS-CoV-2 variants.

6. T Cell Cross-Reactivity between SARS-CoV-2 and Different Vaccines or Pathogens

Given the well-characterised involvement of cross-reactive T cells between HcoVs and SARS-CoV-2 and its variants, other sources of cross-reactivity began to emerge as potentially responsible for cross-reactive T cell immunity to SARS-CoV-2. It was found that HcoVs could not completely explain the cross-reactive memory T cell responses in unexposed individuals to SARS-CoV-2, and, therefore, T cell memory responses from other previous infections or vaccinations also contribute to the cross-reactive T cell response to SARS-CoV-2 [33,42,55,100]. Several notable contributions of memory T cell cross-reactivity between SARS-CoV-2 and the BCG vaccine, influenza A, Measles, Mumps, Rubella vaccine, Paramyxovirus and bacterial pathogens will be explored.

7. T Cell Cross-Reactivity from the Bacillus Calmette–Guérin Vaccine

Early in the COVID-19 pandemic, before SARS-CoV-2-specific vaccines were available, the heterologous BCG vaccination was used as a way to protect people from COVID-19, especially high-risk groups such as frontline healthcare workers and the elderly [101,102]. The heterologous effects of the BCG vaccination have been widely studied, which involved heterologous CD4+ T cell immunity and trained innate immunity, leading to a reduction in all-cause mortality in BCG-vaccinated children and a reduction in respiratory tract infections in adults [103,104,105,106]. Mouse studies have shown that BCG can protect against SARS-CoV-2 and influenza infection via the engagement of the innate and adaptive immune system, particularly CD4+ T helper cells [107]. Clinical trials assessing the outcome of SARS-CoV-2 infection in BCG-vaccinated individuals showed mixed results (Table 2) with 10 trials and retrospective observational studies showing a protective effect (NCT04659941, NCT04369794, NCT04414267, NCT04417335, CTRI/2020/05/025013, NCT04475302, CTRI/2020/07/026668) [108,109,110,111,112,113,114,115,116,117], whereas 7 trials showed no protective effect (NCT04373291, RBR-4kjqtg, NCT04328441, NCT04537663, NCT04648800, NCT04379336, NCT04327206) [118,119,120,121,122,123]. Each study looked at the protective effect that the BCG vaccination has for COVID-19 in different ways, and each study assessed different populations, which may explain the mixed results between trials. Overall, the clinical trials showed that BCG vaccination prior to SARS-CoV-2 infection can induce heterologous immunity including heterologous T cell and antibody responses, which, in some instances, improved COVID-19 outcomes. The development of SARS-CoV-2-specific vaccinations and their global administration and high efficacy has led to a shift away from using the BCG vaccination for protecting against COVID-19.
Increasingly, the involvement of cross-reactive memory T cells is becoming understood as influencing the effect of the BCG vaccination on SARS-CoV-2 infection or vaccination. The analysis of epitopes from BCG proteins has uncovered significant homology to many SARS-CoV-2 epitopes [124,125,126]. There is evidence to suggest that BCG-specific memory T cells can cross-react with SARS-CoV-2-presented epitopes in a TCR-dependent manner [125]. A clinical trial where young adult participants received BCG re-vaccination, followed by SARS-CoV-2 vaccination, showed evidence of an increased benefit from receiving the BCG re-vaccination through enhanced immune responses [127]. In this study, a hallmark of antigen-specific, TCR-dependent memory T cell responses by activation-induced markers (AIM) was observed to be increased in CD4+ and CD8+ memory T cells and BCG-re-vaccinated and SARS-CoV-2-vaccinated individuals. This suggests that TCR-dependent activation of BCG-specific memory T cells by SARS-CoV-2 vaccination may be responsible for enhancing immune responses to SARS-CoV-2 vaccination. The clinical relevance of the TCR-dependent cross-reactivity between the BCG vaccine and COVID-19 has not been fully explored in the completed clinical trials or retrospective observational studies, and as such, further research is required to understand whether this phenomenon is a correlate of protection.
Cross-reactive T cells have been shown to be implicated in reducing the severity of COVID-19 outcomes. In blood samples from a clinical trial, those that received the BCG vaccination and then stimulated with SARS-CoV-2 produced fewer hallmarks of severe COVID-19 through cytokine profiling compared to placebo-vaccination [128]. Additionally, from the same study, BCG vaccination and SARS-CoV-2 stimulation increased the proportion of CD4+ T effector memory cells and CD8+ TEMRA cells and decreased the proportion of naïve T cells compared to placebo vaccination [128]. Another clinical trial where participants received the BCG vaccination then SARS-CoV-2 vaccination showed evidence of an increased benefit from receiving the BCG vaccination [127]. Poly-functional, cross-reactive memory T cells were significantly higher in participants who received the BCG vaccination before the SARS-CoV-2 vaccination, with CD4+ T effector memory and CD8+ TEMRA again being involved. Similar enhanced frequencies of memory T cells were observed in BCG-vaccinated elderly individuals, suggesting that the BCG vaccine can also induce poly-specific memory T cell responses in elderly patients who are at heightened risk of experiencing severe COVID-19 [129]. Overall, this suggests that the memory T cells produced from BCG-vaccination cross-react upon exposure to SARS-CoV-2 infection or vaccination.

8. T Cell Cross-Reactivity from the Influenza Vaccine

Early on in the pandemic, an association between high influenza vaccination coverage and lower SARS-CoV-2 infection rates was observed [130,131,132,133]. Further research showed that influenza A virus epitopes could generate memory T cells that cross-react with SARS-CoV-2 epitopes [35]. This was shown through shared TCR clonotypes and cross-reactive functional cytokine responses between SARS-CoV-2 and influenza A virus epitopes. Therefore, vaccination or exposure to influenza A virus may generate cross-reactive memory T cells that can influence the immune response to SARS-CoV-2 or vice versa. Further research is required to discover whether such cross-reactive T cells are a correlate of protection in COVID-19.

9. T Cell Cross-Reactivity from the Measles, Mumps and Rubella Vaccine

Studies have shown that the measles, mumps and rubella (MMR) vaccine is associated with a better COVID-19 outcome [36,134,135]. Insights into the mechanism behind such cross-protection revealed that individuals vaccinated with the MMR or tetanus, diphtheria and pertussis (Tdap) vaccine shared TCR clonotypes with individuals who were convalescent or vaccinated against SARS-CoV-2 [36]. Furthermore, sequence homologies between MMR surface proteins and SARS-CoV-2 spike have been identified that may give rise to cross-reactive T cells [136,137]. This suggests that T cell cross-reactivity between MMR or Tdap and SARS-CoV-2 may result in a cross-protective effect against COVID-19. More research into the magnitude of the protective role of MMR and Tdap vaccines in terms of SARS-CoV-2 is required.

10. T Cell Cross-Reactivity from Microbial Antigens

Microbial antigens, both pathogenic and commensal, have been shown to exhibit homologies with known epitopes of SARS-CoV-2, giving rise for the potential for cross-reactive memory T cells to be involved in the SARS-CoV-2 immune response [138,139]. This shared homology has previously been shown to generate cross-reactive memory T cells that initially arose from exposure to a bacterial antigen and could become activated after exposure to SARS-CoV-2 epitopes [138,139]. In one study, these memory T cells expressed gut-homing markers, highlighting that they likely arise from microbial antigens from common commensal bacteria [139]. Thus, bacteria may be a source of memory T cells that can cross-react upon exposure to SARS-CoV-2.
Overall, the cross-reactivity from pathogens unrelated to HcoVs may add to the overall cross-reactive memory T cell response in SARS-CoV-2 infection. Further research is needed to understand the contribution of the identified cross-reactive immune responses to overall clinical outcomes in COVID-19 patients.

11. Conclusions and Future Directions

In this study, we have provided an up-to-date account of the mechanisms and role of T cell cross-reactivity in SARS-CoV-2 infection. Such cross-reactivity can arise from pre-exposure to a variety of heterologous pathogens or vaccines. The case for cross-reactive T cell immunity between seasonal HCoVs and SARS-CoV-2 is well established with some degree of cross-protective benefit. A mechanism for T cell cross-reactivity between heterologous vaccinations or other pathogens and SARS-CoV-2 has been established. Further research is required to determine whether the identified cross-reactive T cells from heterologous vaccinations or other pathogens are a correlate of protection in COVID-19.

Funding

This work was supported by the Monash Health Foundation COVID-19 Research Fund grant. P.J.E. received an Australian Government Research Training Program (RTP) scholarship.

Acknowledgments

The authors would like to thank Boaz Ng for the stock image design.

Conflicts of Interest

The authors declare no conflict of interest.

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Biomedicines 12 00564 g001
Figure 1. Mechanism of TCR-dependent T cell cross-reactivity with SARS-CoV-2.
Figure 1. Mechanism of TCR-dependent T cell cross-reactivity with SARS-CoV-2.
Biomedicines 12 00564 g001
Table 2. Clinical trials of the heterologous BCG vaccination for COVID-19.
Table 2. Clinical trials of the heterologous BCG vaccination for COVID-19.
Registry NumberStudy TitlePhase/Country/Participant GroupOutcome
NCT04659941Use of BCG Vaccine as a Preventive Measure for COVID-19 in Health Care Workers (ProBCG)Phase 2
Brazil
Healthcare workers		BCG could protect from COVID-19 [109]
RBR-4kjqtgBCG revaccination of health care professionals working in the COVID-19 pandemic, a preventive strategy to improve innate immune responsePhase 2
Brazil
Healthcare workers		BCG could not protect from COVID-19 [119]
NCT04373291Using BCG Vaccine to Protect Health Care Workers in the COVID-19 PandemicPhase 3
Denmark
Healthcare workers		BCG could not protect from COVID-19 [118]
NCT04414267Bacillus Calmette-guérin Vaccination to Prevent COVID-19 (ACTIVATEII)Phase 4
Greece
Adults ≥ 50 years with comorbidities 		BCG could protect from COVID-19 [110]
NCT04328441Reducing Health Care Workers Absenteeism in COVID-19 Pandemic Through BCG Vaccine (BCG-CORONA)Phase 3
Netherlands
Healthcare workers		BCG could not protect from COVID-19 [120]
NCT04417335Reducing COVID-19 Related Hospital Admission in Elderly by BCG VaccinationPhase 4
Netherlands
Adults ≥ 60 years		BCG could protect from COVID-19. [111]
NCT04537663Prevention Of Respiratory Tract Infection And COVID-19 Through BCG Vaccination In Vulnerable Older Adults (BCG-PRIME)Phase 4
Netherlands
Adults ≥ 60 years with comorbidities		BCG could not protect
NCT04648800Clinical Trial Evaluating the Effect of BCG Vaccination on the Incidence and Severity of SARS-CoV-2 Infections Among Healthcare Professionals During the COVID-19 Pandemic in PolandPhase 3
Poland
Healthcare workers		BCG could not protect from COVID-19 [121]
CTRI/2020/05/025013Phase 2 Clinical Trial for the Evaluation of BCG as potential therapy for COVID-I9Phase 2
India
Adults with COVID-19		BCG could protect from COVID-19 [112]
NCT04475302BCG Vaccine in Reducing Morbidity and Mortality in Elderly Individuals in COVID-19 HotspotsPhase 3
India
Adults 60–80 years		BCG could protect from COVID-19 [113]
CTRI/2020/07/026668To study the effect of BCG vaccine in Reducing the Incidence and severity of COVID-19 in the high-risk population Phase N/A
India
High-risk groups of adults 18–60 years		BCG could protect from COVID-19 [114]
NCT04379336BCG Vaccination for Healthcare Workers in COVID-19 PandemicPhase 3
South Africa
Healthcare workers		BCG could not protect from COVID-19 [122]
NCT04327206BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE)Phase 3
Australia and Netherlands
Healthcare workers		BCG could not protect from COVID-19 [123]
NCT04369794COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement (BATTLE)Phase 4
Brazil		BCG could protect from COVID-19 [108]
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Eggenhuizen, P.J.; Ooi, J.D. The Influence of Cross-Reactive T Cells in COVID-19. Biomedicines 2024, 12, 564. https://doi.org/10.3390/biomedicines12030564

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Eggenhuizen PJ, Ooi JD. The Influence of Cross-Reactive T Cells in COVID-19. Biomedicines. 2024; 12(3):564. https://doi.org/10.3390/biomedicines12030564

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Eggenhuizen, Peter J., and Joshua D. Ooi. 2024. "The Influence of Cross-Reactive T Cells in COVID-19" Biomedicines 12, no. 3: 564. https://doi.org/10.3390/biomedicines12030564

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