Cell-mediated immunity may be more important than neutralizing antibodies in COVID-19 outcome

An interesting new study sheds light on some important differences between asymptomatic and symptomatic patients with coronavirus disease 2019 (COVID-19). The preprint, which appeared on the medRxiv* preprint server in December 2020, adds important details to the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study details

The study included 193 patients with SARS-CoV-2 infection in two Chinese cities, between January 21 to March 6, 2020. These included 31 asymptomatic carriers, 14 presymptomatic patients, and 149 symptomatic patients.

There were four family clusters in the study, with 15 subjects infected among them. Of these, 3 were children 12 years or less, 3 were adults between 18 and 60 years, while one was a woman of 75 years.

Among the 8 symptomatic cases, 4 were older than 60 years, and had severe infection. Of these severely ill patients, three had existing comorbidities. The other 4 had mild illness, and were aged between 18 and 60 years, and only 1 had other chronic conditions.

Poor antibody response in asymptomatic patients

The researchers found that asymptomatic infections occurred in younger patients, who had higher white cell and lymphocyte counts, lower C-reactive protein levels, and lower viral loads. They also cleared the virus faster, as shown by the faster cessation of viral shedding. More patients who acquired the infection from household contacts had asymptomatic infection compared to symptomatic patients, at around 90% vs around 60%, respectively.

After seroconversion occurred, IgM-positives became IgM-negative more rapidly in asymptomatic carriers, compared to COVID-19 patients (7.5 days and 25.5 days, respectively). IgG seroconversion occurred at equal velocities in both groups. However, IgG positivity persisted in two-thirds of asymptomatic carriers compared to a third of symptomatic COVID-19 patients.

In symptomatic patients, viral loads were higher relative to presymptomatic patients. The latter also shed virus longer than asymptomatic individuals. Thus, asymptomatic carriers appear to show evidence of higher antiviral immunity resulting in more rapid clearance of the virus, compared to symptomatic patients. This immunity does not appear to be the result of antibody-mediated responses, since both IgM and IgG were showing more rapid rates of decline in asymptomatic carriers rather than in COVID-19 patients.

Effective immune response mostly cellular

These data indicate that humoral immunity against SARS-CoV-2 was not efficiently aroused by a relative short exposure of SARS-CoV-2 in asymptomatic carriers or in those with a stronger innate and cell immunity.”

Instead, “innate immunity and cell-mediated immunity should play key roles in repressing viral replication in asymptomatic carriers,” as indicated by the lower viral load and shorter period of viral shedding in asymptomatic patients. A higher viral load is indicative of a higher risk of poor COVID-19 outcomes.

In earlier research, the authors demonstrated that progressive COVID-19 disease occurs in patients with lower T cell counts in the blood, fewer CD4+ T cells and CD8+ T cells. On the other hand, the proportion of circulating neutrophils is higher in these patients, with a higher ratio of neutrophils to lymphocytes. Inflammatory markers like IL-6 (interleukin-6), C-reactive protein (CRP), and procalcitonin are raised as well.

Effector T cell exhaustion is thought to be key in the development of severe or critical COVID-19. This is supported by other studies showing low levels of natural killer (NK) cells, and CD4+, CD8+ and CD3+ T cells. In the convalescence period, however, there is a marked and rapid expansion of highly cytotoxic effector T cells belonging to CD4+effector-granulysin, CD8+ effector-granulysin, and NKT CD160 cells. Both innate and T cell immunity is therefore impaired in progressive COVID-19, which may be due to high levels of systemic inflammation. The level of systemic inflammation in asymptomatic carriers is also lower.

What are the implications?

Approximately 3 of every 4 patients with SARS-CoV-2 infection, asymptomatic or otherwise, did not develop IgG in the incubation period or afterward. Thus, the role of humoral immunity is suspect. The fact that IgG seroconversion from positive to negative, or to weak positive, is only about 30% in a period of 160 days from the diagnosis, shows that anti-SARS-CoV-2 IgG levels wane significantly following infection. While this occurred in over a half of asymptomatic patients, it was seen in a quarter of symptomatic patients. This finding has been reported in health workers on the front line in the US and in France.

These findings draw attention to the importance of eliciting specific cell-based immunity to SARS-CoV-2 rather than neutralizing antibodies. Vaccine efficacy should therefore be assessed in relation to the ability of the vaccine to induce cellular immunity.

*Important Notice

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.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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