The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection.
In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms.
We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection.
SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time.
The data presented here show that 82·0% of recovered COVID-19 patients had N-IgG antibodies, 95·2% had S-IgG antibodies, 94·2% had RBD-IgG antibodies, and 81·6% had neutralising antibodies 12 months after a SARS-CoV-2 infection. Although the decline in neutralising antibody titres between 6 and 12 months after infection mainly occurred in older people and critical patients, seropositivity of neutralising antibodies was stable in this population. Virus-specific T cells were detectable in all patients that had recovered from COVID-19. Both the D614G and the delta variants escape from the neutralising antibodies against the original strain, an effect that depends on neutralising antibody titres. By contrast, an absence of response to the beta variant is not related to neutralising antibody titres against the original strain. Importantly, although neutralising antibody responses are less efficient to this variant, T-cell responses are cross-reactive to the beta variant in patients recovered from infection. Memory T cells retained the ability to mediate cellular immunity in patients who had lost their neutralising antibody responses.
At present, long-term immune responses in recovered patients have been investigated. Cohen and colleagues observed that broad and effective antibody responses, and memory B-cell and T-cell responses, might persist for 8 months following SARS-CoV-2 infection.Li and colleagues found that the positive rate of RBD-IgG exceeded 70% 12 months after diagnosis.However, they did not evaluate the T-cell responses to SARS-CoV-2 and neutralising antibody responses to variants. Rank and colleagues found that about two-thirds of participants maintained IFNγ-specific T-cell responses at the 12-month follow-up. The antiviral T cells were lower in frequency than those in this study.
The major reason for this discrepancy might be because we used in-vitro expanded short-term T-cell lines after peptide pool stimulation. Recently, Zhang and colleagues reported that SARS-CoV-2-specific cellular and humoral immunities are durable 1 year after disease onset, and PBMCs were expanded for 9 days in vitro.
The results were similar to our findings. However, the neutralising antibody and T-cell responses to SARS-CoV-2 variants were not assessed in the study by Zhang and colleagues.
SARS-CoV-2 variants, especially alpha, beta, gamma, delta, and omicron, have been associated with rapid increases in cases at multiple locations.
These variants harbour mutations in the Spike protein that might alter virus–host cell interactions and escape neutralising antibody responses. Because beta is the most probable variant to escape the approved vaccines in comparison with the alpha, gamma, and delta variants,23 we evaluate the neutralising antibody and T-cell responses to the beta variant in this study. Our data showed that neutralising antibodies from individuals who had recovered from natural infection against the original strain are less able to neutralise effectively the D614G, beta, and delta variants. However, higher neutralising antibody titres against the original strain contributed to the protection from infection of D614G and delta variants in vitro. Neutralising antibodies against the original strain had a lower ability to neutralise the beta variant than the D614G and delta variants. The ability to escape from the neutralising antibodies against the original strain has no association to antibody titres, suggesting that the beta variant affects the binding of neutralising antibodies to the viral Spike protein. Structural information provides a basis for how SARS-CoV-2 variants have evolved to evade the immune system. The three mutations characterising the beta variant (K417N, E484K, and N501Y) are located at the receptor-binding domain, making the variant resistant to some potent neutralising antibodies.
However, the D614G variant enhances infectivity mainly through increasing the stability of the trimer, rather than through more exposed receptor-binding domains.Recently, a new SARS-CoV-2 variant (omicron [B.1.1.529]) was reported.How it interacts with immune cells needs to be assessed. Current SARS-CoV-2 vaccines are mainly focused on neutralising antibodies induced by the viral Spike or receptor-binding domain protein. However, mutations in the Spike protein can cause epitope changes, potentially resulting in the virus escaping from neutralising antibodies. It has been reported that the beta and gamma variants could not be efficiently blocked by plasma from convalescent patients with COVID-19 and serum from individuals vaccinated with the BNT162b2 vaccine (tozinameran, Pfizer–BioNTech),indicating that vaccine efficacy could be compromised by the emergence of viral variants. Although neutralising antibodies were less efficient at mediating in-vitro protection in naturally infected individuals, we found that the beta variant seemed to have no substantial impact on cellular immune responses 12 months after infection. Thus, the lack of sufficient neutralising antibodies against SARS-CoV-2 variants in individuals recovered from previous SARS-CoV-2 infection could be mitigated by T-cell responses. Despite the existence of cellular immune responses, it is urgent to use viral targets that are less likely to mutate for future SARS-CoV-2 vaccine platforms.
Our findings indicate that SARS-CoV-2 cellular immunity decays more slowly over time than neutralising antibody titres. In addition, SARS-CoV memory T cells have been detected 17 years after infection in individuals who recovered from SARS, and displayed robust cross-reactivity to SARS-CoV-2.It has been reported that in the absence of neutralising antibodies, T-cell memory correlates with protection from influenza disease severity in humans.Future studies are needed to evaluate the role of T-cell memory of SARS-CoV-2 in protection against reinfections.
Our study has several limitations. First, we did not obtain consecutive samples. Longitudinal data from cohorts will help to further analyse the SARS-CoV-2 humoral and cellular immunity in individuals recovered from COVID-19. Second, because moderate-to-critical cases represent most inpatients, asymptomatic and mild cases are not included here. Third, we evaluated neutralising antibody responses to the D614G, beta, and delta variants, and the cellular responses to the beta variant. Further studies should be done to characterise humoral and cellular immunity against other SARS-CoV-2 VOCs. In addition, because of the ethical limitations to sampling, we were not able to obtain enough samples for T-cell analysis. Instead, we cultured PBMCs in vitro before analysing T-cell responses in ELISpot assays, as described previously.17 This expansion protocol could potentially alter both the magnitude and polyfunctionality of the T cells due to differences in the proliferative capacity of different antigen-specific T cells.
In summary, we evaluated antibody and cellular immunity in COVID-19-convalescent individuals 12 months after infection. Our findings show that humoral and cellular immunity against SARS-CoV-2 is present in most recovered patients 12 months after moderate-to-critical infection. Neutralising antibody responses to the D614G, beta, and delta variants are much poorer than those to the original strain from Wuhan, China. Our results also showed the presence of cellular immune responses to SARS-CoV-2 variants and patients who lost their neutralising antibody responses. These data underline the importance of broad B-cell and T-cell immunity for future vaccine strategies targeting SARS-CoV-2.
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