ABSTRACT
Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here, we examined the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) using high-resolution, single-cell multiomics and flow cytometry. We confirmed that iLD-IL-2 selectively expands thymic-derived FOXP3 + HELIOS + Tregs and CD56 br NK cells, and showed that treatment reduced the frequency of IL-21-producing CD4 + T cells and of two subsets of innate-like CD8 + T cells, mucosal-associated invariant T cells and V γ9 V δ2 T cells. The cellular changes induced by LD-IL-2 were associated with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. The anti-inflammatory nature of this gene expression signature was supported by the observation that the same genes were also modulated in COVID-19 patients, but in the opposite direction. These findings warrant continued investigations of the potential clinical benefits of iLD-IL-2 in immunotherapy and further understanding of the development of long-term sequelae in convalescent COVID-19 patients.
Subject(s)
COVID-19ABSTRACT
ObjectivesTo assess T cell responses in individuals with and without a positive antibody response to SARS-CoV-2, in symptomatic and asymptomatic individuals during the COVID-19 pandemic. MethodsParticipants were drawn from the TwinsUK cohort, selected according to a) presence or absence of COVID-associated symptoms (S+, S-), logged prospectively through the COVID Symptom Study app, and b) Anti-IgG Spike and anti-IgG Nucleocapsid antibodies measured by ELISA (Ab+, Ab-), during the first wave of the UK pandemic. T cell helper and regulatory responses after stimulation with SARS-CoV-2 peptides were assessed. Results32 participants were included in final analysis. 14 of 15 with IgG Spike antibodies had a T cell response to SARS-CoV-2-specific peptides; none of 17 participants without IgG Spike antibodies had a T cell response (Chi-squared 28.2, p<0.001). Quantitative T cell responses correlated strongly with fold-change in IgG Spike antibody titre (rho=0.79, p<0.0001) but not to symptom score (rho=0.17, p=0.35). ConclusionsHumoral and cellular immune responses to SARS-CoV-2 are highly correlated, with no evidence that cellular immunity differs from antibody status four months after acute illness.
Subject(s)
COVID-19ABSTRACT
Background: Cancer patients are vulnerable populations for COVID-19 complications and mortality. We previously reported on the poor single-dose immunogenicity of BNT162b2 mRNA vaccine in cancer patients, particularly those with haematological malignancies. Methods: In this prospective, observational study relating to the safety and immunogenicity of BNT162b2 mRNA vaccine, 201 vaccinated cancer patients (solid cancer n=125; haematological cancer n=76) and 54 healthy controls (mostly health-care workers “HCW”) were recruited between December 8th, 2020, and April 23rd, 2021. The previously reported interim results covered a period of 101 days since first patient recruitment, during which time 47 subjects received a second “boost” vaccination on day 21. Because of the change in UK Government policy, all others received a delayed vaccine boost at about 12 weeks after their first vaccination, and had their blood sampled 2 weeks’ later. Here, we describe immunogenicity data following the delayed boost in 31 HCWs, 72 solid cancer and 56 haematological cancer patients. Seroconversion, virus neutralisation, and T cell assays were as described previously, with an additional test for neutralisation of the B.1.617.2 (delta) variant-ofconcern (VOC). The primary endpoint of the study was the impact on seroconversion following delayed (>21days) vaccine boosting in solid and haematological cancer patients. The secondary endpoints were: safety following delayed vaccine boost; T cell responses; and neutralisation of SARS-CoV-2 Wuhan (“wild type” [WT]), B.1.1.7 (alpha), and B.1.617.2 (delta) variants.Findings: Delayed (>21days) boost vaccination of solid cancer patients and haematological cancer patients with the BNT162b2 vaccine was well tolerated, as the primary vaccination had been. There was no vaccine-associated death. Boosting significantly increased solid cancer patients’ seroconversion responses, that had been strikingly poor in response to a single dose: from 38% to 84%. Boosting also significantly improved vaccine immunogenicity for haematological cancer patients, but most (57%) still failed to seroconvert. Seroconversion correlated strongly with the capacity to neutralise SARSCoV- 2 cell entry, although neutralisation of the WT variant was typically greater than of the VOC. Neutralisation was significantly increased by boosting for HCWs but not for cancer patients. In comparison to seroconversion, boosting achieved higher rates of functional T cell responsiveness (de novo responses) but had little impact on the magnitude of T cell responses for those who had responded to first-dose vaccination. When patients were scored as showing both seroconversion and T cell responses, the unfavourable situation of haematological cancer patients was overt with only 36% (12/33) defined as being responders compared to 78% (25/32) of solid cancer patients and 88% (15/17) of HCWs. There was no significant difference in any aspect of immunogenicity for HCWs or solid cancer patients receiving the delayed boost versus the day 21 boost (this comparison could not be made for haematological cancer patients because too few received an early boost). Chemotherapy within 15 days either side of the boost exacerbated the likelihood of non-responsiveness to the vaccine.Interpretation: Boosting at either 3 weeks or longer (up to 12 weeks) post-primary vaccination shows high efficacy in terms of seroconversion of solid cancer patients and increases in their SARS-CoV-2 Spike-specific antibody titres. By contrast, delayed boosting left most haematological cancer patients without serological protection against SARS-CoV-2 infection. These data support the ongoing adjustment of health care measures to limit the evident vulnerability of such individuals to SARS-CoV- 2, and to limit their potential to transmit virus variants that might develop in the context of absent or partial immunoprotection. The absence of any clear improvements in immunogenicity of a delayed boost relative to boosting on day 21 emphasizes the importance of early boosting for cancer patients, and potentially of doing so repeatedly, particularly given how well the vaccine was tolerated. Chemotherapy, if possible should be withheld 15 days before and 15 days after the vaccination date.Trial Registration: The trial is registered with the NHS Health Research Authority (HRA) and Health and Care Research Wales (HCRW) (REC ID: 20/HRA/2031).Funding: KCL, CRUK, Leukemia & Lymphoma Society, Wellcome Trust, Rosetrees Trust, Francis Crick Institute.Declaration of Interest: None to declare. Ethical Approval: The trial was approved by the institutional review boards of the participating institutions (IRAS ID: 282337 REC ID: 20/HRA/2031).