Silent battles: immune responses in asymptomatic SARS-CoV-2 infection

Abstract

SARS-CoV-2 infections manifest with a broad spectrum of presentations, ranging from asymptomatic infections to severe pneumonia and fatal outcomes. This review centers on asymptomatic infections, a widely reported phenomenon that has substantially contributed to the rapid spread of the pandemic. In such asymptomatic infections, we focus on the role of innate, humoral, and cellular immunity. Notably, asymptomatic infections are characterized by an early and robust innate immune response, particularly a swift type 1 IFN reaction, alongside a rapid and broad induction of SARS-CoV-2-specific T cells. Often, antibody levels tend to be lower or undetectable after asymptomatic infections, suggesting that the rapid control of viral replication by innate and cellular responses might impede the full triggering of humoral immunity. Even if antibody levels are present in the early convalescent phase, they wane rapidly below serological detection limits, particularly following asymptomatic infection. Consequently, prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus.

Keywords: COVID-19; antibody; asymptomatic; cellular immunity.

Fig. 1. Ratio between the prevalence of antibodies and the total number of reported cases in different geographical regions.

The median ratio between corrected seroprevalence estimates from national studies and the corresponding cumulative incidence of SARS-CoV-2 infection from nine days prior. Includes studies (n = 49) from January to December 2020. Data from (Bobrovitz et al. PLoS One. 2021) [23]

Fig. 2. COVID-19 infection–fatality ratio by age and geography.

A COVID-19 infection–fatality ratio estimates by age (linear scale). B COVID-19 infection–fatality ratio estimates by age (log scale). C COVID-19 infection–fatality ratio by location; 1. January 2021. All data from (COVID-19 Forecasting Team. Lancet. 2022) [32]

Fig. 3. Proportion of asymptomatic and symptomatic SARS-CoV-2 infection by age and geography.

A Proportion of SARS-CoV-2 infected cases with asymptomatic, mild to moderate, and severe to critical symptoms in different age groups. Figure adapted from (Yan et al. Front Med. 2020) [35]. B Proportion of SARS-CoV-2 infected pediatric cases with asymptomatic, mild to moderate, and severe to critical symptoms in different age groups. Figure adapted from (Li et al. Ann Acad Med Singap. 2020) [37]. C Proportion of asymptomatic SARS-CoV-2 infections in different geographic regions. Data from (Chen et al. BMJ Open. 2021) [39]

Fig. 4. Immune responses in asymptomatic and symptomatic SARS-CoV-2 infection.

A Immunity characterizing asymptomatic SARS-CoV-2 infection. B Asymptomatic SARS-CoV-2 infection is associated with early and robust interferon and T cell responses, and low antibody titers (left). Symptomatic SARS-CoV-2 infection is associated with delayed interferon and T cell responses, and higher antibody titers (left)

Fig. 5. Estimating infection rates among asymptomatics by measuring SARS-CoV-2-specific antibodies and T cells.

A Kinetics and magnitude of SARS-CoV-2-specific antibodies and T cells following an asymptomatic SARS-CoV-2 infection. B Detection of SARS-CoV-2-specific antibodies and/or T cells among asymptomatic Kenyans with unknown infection status. Data from (Samandari et al. J Clin Invest. 2023) [96]