In a recent study posted to medRxiv* preprint server, researchers evaluated antibody responses in mild cases of coronavirus disease 2019 (COVID-19).
Currently, the risk of reinfection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) ranges from 0% to 19.5% for 10 months after infection, indicating that protective immunity develops and is sustained post-infection. Various studies in animal models and humans have revealed that antibodies and B and T lymphocytes are vital to the protection and immune memory. Further, the quantity and quality of these immune responses are pivotal to long-term immunity, but the underlying mechanisms remain unclear yet.
Age is an essential factor driving the outcome of diseases including COVID-19. Different studies have observed functional cellular and humoral responses among children against SARS-CoV-2 who primarily develop mild or asymptomatic disease. According to several reports, polyfunctional antibodies neutralize SARS-CoV-2 entry and recruit innate immune effectors such as neutrophils, complement systems, natural killer (NK) cells, and monocytes. These polyfunctional antibodies were inversely correlated with the severity of disease post-infection, indicative of diverse humoral responses.
Also, qualitative features are just as crucial as neutralizing responses and titers. Similarly, clusters of differentiation 4 (CD4) and CD8 T cell responses to SARS-CoV-2 are variable across people. Nevertheless, the factors driving the diverse immune responses against SARS-CoV-2 remain poorly defined.
The study and findings
The current study evaluated immune responses to COVID-19 and compared them as a function of age between non-hospitalized COVID-19 patients and healthy SARS-CoV-2-naïve subjects.
Ninety-one subjects from 45 households were recruited between June 2020 and March 2021, with each completing a survey for data on demographics, infection history, and clinical symptoms. Although 10 subjects required emergency services for illness, none were hospitalized. COVID-19 was confirmed in 67 participants by a polymerase chain reaction (PCR) test, spike (S) or nucleoprotein (N)-specific immunoglobulin G (IgG) detection, or viral RNA detection in plasma, while the remaining subjects had no evidence of COVID-19.
The humoral immune responses against SARS-CoV-2 were qualitatively and quantitatively profiled. The researchers estimated the plasma levels of IgG (IgG1 – IgG4), IgA (IgA1 and 2), and IgM specific to SARS-CoV-2 S and N proteins, and seasonal coronaviruses (CoVs) such as HKU1, OC43, NL63, and 229E. COVID-19 patients had significantly elevated levels of SARS-CoV-2-specific antibodies than controls, and no such differences (in antibody levels) were evident for seasonal CoVs. Most infected subjects neutralized pseudoviruses coated with SARS-CoV-2 D614G S protein, yet 29.8% of infected individuals had no neutralizing antibodies (nAbs).
Peripheral blood mononuclear cells (PBMCs) isolated from all subjects were stimulated in vitro with peptide pools of SARS-CoV-2 S, N, and matrix (M) proteins. Both CD4 and CD8 T cell activation-induced marker expression (AIM) was significant in infected participants compared to controls. CD4 T cell AIM responses remained stable for over six months in those who followed up. Some infected participants exhibited T cell responses despite no noticeable antibody responses.
Further, cytokine and chemokine responses were measured in peptide-stimulated PBMCs and compared to controls (non-stimulated PBMCs). In response to S and N but not M antigens, the secretion of interleukin (IL)-2 and interferon (IFN)-γ was Th1-biased in infected individuals. Increased age correlated strongly with increases in S-specific IgG1, nAbs, IL2, CD8 T cell activation, perforin, and granzyme B levels.
Further investigations revealed two distinct populations among those infected. Population 1 showed typical SARS-CoV-2 immune responses such as CD4+ AIM, IL2 secretion, antiviral antibody functions, and increased IgM levels to SARS-CoV-2 or seasonal CoVs. In contrast, population 2 demonstrated a non-classical, Th2-biased response like the secretion of IL4, IL10, and IL13, higher IgG2, and IgG4 to the receptor-binding domain (RBD) of S protein. Thirty-two COVID-19 patients were subsequently vaccinated with Pfizer, Moderna, or J & J vaccines. The team noted a significant boost in nAb levels post-vaccination, albeit a waning of immune responses with time was evident. Moreover, between the two populations, population 1 demonstrated higher post-vaccination nAb titers than population 2.
Based on the findings, the researchers noted that age and CD4+ Th1 responses were associated with qualitative features of humoral immunity against SARS-CoV-2. The immune responses were significantly diverse among the infected cohort, including some who did not develop nAbs. Age was significantly correlated to many immunological measures.
Age-associated immune responses against SARS-CoV-2 were mainly related to Ig isotypes produced during infection. To summarize the findings, humoral immune responses and effector functions to SARS-CoV-2 were shaped by age, COVID-19 severity, and CD4+ Th cell responses quality.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.