Durability of Immunity to SARS-CoV-2 and Other Respiratory Viruses

Abstract

Even in nonpandemic times, respiratory viruses account for a vast global burden of disease. They remain a major cause of illness and death and they pose a perpetual threat of breaking out into epidemics and pandemics. Many of these respiratory viruses infect repeatedly and appear to induce only narrow transient immunity, but the situation varies from one virus to another. In the absence of effective specific treatments, understanding the role of immunity in protection, disease, and resolution is of paramount importance. These problems have been brought into sharp focus by the coronavirus disease 2019 (COVID-19) pandemic. Here, we summarise what is now known about adaptive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and draw comparisons with immunity to other respiratory viruses, focusing on the longevity of protective responses.

Keywords: COVID-19; SARS-CoV-2; immune responses; immunity; infection; respiratory viruses.

Figure 1

Immunity upon Re-exposure to a Virus in the Respiratory Tract. (1) Mucosal antibodies (predominantly dimeric IgA), produced constitutively by plasma cells resident in the respiratory tract, can efficiently neutralise virus. (2) Systemic antibodies, (mostly high-affinity IgG) are constantly produced by long-lived plasma cells in the bone marrow. These antibodies can move from the blood into the respiratory tract, through transcytosis and transudation, to neutralise virus, as well as mediating other Fc-dependent antiviral effector functions. (3) Tissue-resident CD4⁺ and CD8⁺ T cell populations are rapidly activated to mediate immune-coordination and antiviral activities in situ. (4) Viral antigens from the respiratory tract transit, freely in lymph or carried by dendritic cells, to secondary lymphoid organs. Here, long-lived recirculating memory T and B cell populations are activated and mount rapid recall responses. (5) Once large numbers of effector cells have proliferated from memory T cell precursors they home to the respiratory infection site. (6) While most memory B cells proliferate into antibody-producing plasma cells, some re-enter germinal-centre reactions to replenish the memory B cell pool. Through affinity-maturation and somatic hypermutation, germinal-centre reactions evolve the potency and breath of the antibody response. (7) Newly created antibody-secreting plasma cells traffic to sites, including the bone marrow and mucosa-associated lymphoid tissue, where they can reside long-term. Abbreviation: T_RM cells, tissue-resident T memory cells.

Figure 2

Contributions of Adaptive Immune Responses to Protection against Respiratory Viruses in Durable and Transient Responses. (A) In a transient immune response, levels of neutralising antibodies are lower but typically still initially provide sterilizing immunity against homologous virus. Subsequent waning reduces levels below the threshold for sterilising immunity within a few years. In the absence of sterilizing immunity, T memory and T resident memory cell populations, though smaller than following a robust response, can contribute functional protection to lessen disease severity upon reinfection with either homologous or variant virus. (B) In a durable immune response, high levels of neutralising antibodies mediate sterilizing immunity that prevents reinfection with homologous virus. Despite rapid waning over the initial months, antibodies decay slowly thereafter, maintained at a protective level for many years by long-lived plasma cells. Recirculating memory T cells are also long-lived and contribute functional protection which can lessen disease severity caused by viral variants that escape antibody-mediated immunity. Rapid responses of tissue-resident memory cells (T_RM) contribute robust immunity in the months following initial infection; however, these populations are currently thought to be relatively short lived in the absence of repeated stimulation.