▎ WuXi AppTec content team editor
The body's immune response to the new crown virus has many aspects, in addition to producing neutralizing antibodies, it will also stimulate T cell responses and immune memory against the new crown virus. Memory immune response is essential to prevent reinfection and reduce disease severity, and exploring these mechanisms can also help provide a scientific basis for vaccination strategies.
A few days ago, a blockbuster study jointly led by Professor Cao Bin, Vice President of China-Japan Friendship Hospital, and Professor Wang Jianwei, Vice President of Peking Union Medical College of the Chinese Academy of Medical Sciences, was recently published in The Lancet Microbe.
Based on data from people who have recovered from COVID-19 in the early stages of the outbreak, the analysis found that the levels of COVID-19-specific neutralizing antibodies and T cell responses were generally stable within 1 year after initial infection. However, the antibody was less effective at neutralizing other variants than the original strain, while memory T cell responses were not significantly affected by the variants. These results underscore the importance of cross-protection of specific T cell responses in preventing severe disease caused by variants.
Screenshot source: The Lancet Microbe
Previous studies have suggested that the level of COVID-19-specific antibodies in infected people will gradually decrease within a few months, but B cells, CD4 T cells, and CD8 T cells play an important role in the memory immune response after natural infection. However, our current understanding of the characteristics of the immune response 1 year after the initial infection with the new crown virus is still very limited. At the same time, there is a lack of clear conclusions about whether long-term immunity can help the body resist the emerging covid-19 variants.
To better answer these questions, the research team conducted this longitudinal cohort study to analyze the immunity of people who have recovered from COVID-19 12 months after initial COVID-19 infection, including the persistence and functionality of humoral immune responses and T cell responses to the original strains and variants (D614G, Beta, and Delta). Humoral immune responses include IgM, IgA, and IgG antibodies against the coronavirus nuclear protein, spike protein, and receptor-binding domains.
A total of 1,096 COVID-19 recovery patients who were discharged from hospital between 7 January and 29 May 2020 were included in the study, of which 289 (26.4%) were initially moderate (admitted but did not require supplemental oxygen), 734 (67.0%) were initially diagnosed with severe illness, and 73 (6.7%) were initially diagnosed with critical illness. These patients were followed up from 16 December 2020 to 27 January 2021. None of these patients had a repeat infection during the follow-up period and had not been vaccinated at the time.
Plasma samples were taken from all 1096 patients for antibody assays (USing the ELISA method). 141 patients were provided with a pair of plasma samples for neutralizing antibody analysis, of which 92 were provided with peripheral blood mononuclear cells (PBMCs) for the determination of T cell responses.
Long-term immunity to the original strain
The results showed that at 12 months after the initial infection, different antibodies could be detected in most people, including N-IgG antibody (82.0%), S-IgG antibody (95.2%), RBD-IgG antibody (94.2%) and neutralizing antibody (81.6%). S-IgG antibody titers were higher in severely ill patients than in moderately symptomatic patients; at 12 months, IgG titers increased with age.
In most individuals under the age of 60, neutralizing antibody levels remain stable at 6 and 12 months after initial infection.
The overall antibody positivity rates at 6 months and 81.6% at 6 months and 12 months were 85.8% and 81.6%, respectively, with no difference between different disease levels and different age groups.
In moderately ill and severely ill patients, as well as in the 18–44 and 45–59 age groups, neutralizing antibody titers at 12 months did not differ much from 6 months. In critically ill patients and in the ≥ 60-year-old age group, neutralizing antibody titers decreased significantly over time.
▲Neutralizing antibody positive rate (A) and titer (B) at 6 months after infection, 12 months, and changes in neutralizing antibody titer in different disease (C) and different age groups (D). (Image source: References[1])
Memory T cell responses (at least one specific protein of the new coronavirus) were detected in 90% (72 cases/80 cases) of the recovered, and overall, T cells responded to all detected new coronavirus proteins. There were no significant differences in the magnitude of T cell responses or the size of cytokine profiles (IFN-γ, IL-2, and TNFα) in individuals with varying severity of disease.
Memory T cell responses of each individual (A), patients with different disease severity (B), and T cell responses to different proteins of the new crown virus (Image source: Reference [1])
Long-term immunity to different variants
Next, the team evaluated the immune response of antibodies and T cells in the recovered to the D614G, Beta and Delta variants through in vitro experiments.
The ability of antibodies to neutralize the virus is weakened
At 12 months after initial infection, 115 of the 141 people who provided samples with the corresponding tests (82%) had neutralizing antibodies against the original strain. In contrast, immune escape occurred in all three variants: only 68 people (48 percent) had neutralizing antibodies against D614G, 32 (23 percent) had neutralizing antibodies against the Beta variant, and 69 people (49 percent) had neutralizing antibodies against the Delta variant.
Neutralizing antibody titers against all three variants were also significantly reduced.
The reduction in neutralizing antibody titers was similar to that of the D614G variant and the Delta variant, and the decrease in neutralizing antibody titers was even greater for the Beta variant.
The degree of reduction of the immune response to the D614G and Delta variants induced by the original strain, related to the titer of the neutralizing antibody after infection with SARS-CoV-2, regardless of age;
Immune escape from the Delta variant is more common in the 18–44 and 45–59 age groups.
▲ Neutralizing antibody weakens the ability of the neutralizing antibody to the three variants (Image source: Reference[1])
Cellular immunity is still strong
But further analysis found that in most individuals, T cells had a cross-immune response to the Beta variant, and that the Beta variant could induce a stronger cytokine response: a stronger TNFα response in the CD4 T cell response and a stronger IFNγ response and a TNFα response in the CD8 T cell response.
▲T cells respond similarly to the original strain and beta variant spike protein (Image source: Reference[1])
At 12 months post-infection, the amplitude of the T cell response was independent of neutralizing antibody titers, S-IgG, N-IgG, and RBD-IgG antibody titers.
What's more, the T cell response was detectable in all 16 tested individuals whose neutralizing antibodies had been negative 12 months after the initial infection.
Implications for vaccine strategies
The paper concludes that these data have important reference significance for vaccine efficacy under variant epidemics. In particular, some patients still have a cellular immune response in the case of losing neutralizing antibody response to the new crown variant, which suggests that B-cell and T-cell immunity is very important for the new crown vaccine strategy, and cross-protection of the new crown virus-specific T cell response is very important for preventing severe disease caused by the variant. In addition, we need continuous monitoring to assess the duration of immunity and the response of antibodies and T cells to the CORONAVIRUS variant.