Are We Forgetting About IgA? A Re‐examination of Coronavirus Disease 2019 Convalescent Plasma

Abstract

Background While convalescent plasma (CP) may benefit patients with COVID‐19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG‐specific anti‐SARS‐CoV‐2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. Study design and methods Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti‐SARS‐CoV‐2 antibody titers against the receptor‐binding domain responsible for viral entry. Symptom onset was obtained by chart review. Results Increased IgA anti‐SARS‐CoV‐2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID‐19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. Conclusions IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID‐19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.

Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma

“…IgM and IgG have been widely implicated in effective neutralisation of SARS-CoV-2 (Gasser et al, 2021;Lopez et al, 2021;Natarajan, Xu, et al, 2021;Wheatley et al, 2021). However, throughout the COVID-19 pandemic, the study of anti-SARS-CoV-2 IgA responses have been relatively neglected (Verkerke et al, 2021). The plasma IgA response to SARS-CoV-2 peaks during acute infection but is relatively transient in nature, dominating the acute plasma neutralising response with a 2 phased decay in antibody binding to spike (half-life of 42 days in the first 60 days and >1000 days from 60-160 days post symptom onset) (Sterlin et al, 2021;Wheatley et al, 2021).…”

“…IgG has been shown to play a critical role in plasma neutralisation to various viral infections, including SARS-CoV-2 (W. T. Lopez et al, 2021;Maeda et al, 2021). However, the contribution of plasma IgA to the convalescent SARS-CoV-2 neutralising antibody response, especially to emerging RBD mutants remains unclear (Sterlin et al, 2021;Verkerke et al, 2021;Wang et al, 2021). To define the contribution of IgG and IgA to the neutralising capacity of convalescent plasma, we depleted IgA from plasma (IgA-plasma) and also depleted plasma of both IgA and IgG (IgA-and IgG-depleted plasma) to assess the capacity of antibody depleted plasma fractions to inhibit RBDWT binding to ACE2 (fig.…”

Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

“…Natural SARS-CoV-2 infection usually resolves with the appearance of serum monomeric IgA. In fact, much of the neutralizing activity in convalescent plasma resides in the IgM and IgA fraction [39,40]. However, while serum IgG to Spike protein is still present in 92% of the participants after 7 months, serum IgA (and IgM) antibodies decline rapidly after the first month post onset of disease [41][42][43].…”

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

“…The quality and quantity of these factors other than IgG neutralizing titers are not typically used to qualify potential convalescent plasma. This could significantly underplay the potential of CPT, as it has been demonstrated, for example that both neutralizing IgM [ 159 ] and IgA [ 160 ] titers in convalescent plasma were correlated with better outcomes in COVID-19 patients treated with CPT. CPT has the potential benefits of not only direct neutralization of virus binding to receptor, but also immunological activity of the various antibody isotypes, including ADCC (primarily IgG1 and IgG3 isotypes), antibody dependent cellular phagocytosis (ADCP; all IgG isotypes); complement mediated cytotoxicity (CDC; IgG1, IgG2, IgG3, and IgM isotypes) [ 161 ].…”

“…In another study, Bégin et al [ 141 ] demonstrated that the level of ADCC induced by IgGs in plasma was correlated directly with outcomes. Other potential factors with the quality of convalescent plasma used to treat COVID-19 that have not been fully analyzed are titers of neutralizing IgM [ 159 ] and IgA [ 160 ] isotypes, and levels in the convalescent plasma of other potentially protective factors, such as IL-1β, IL-2, IL-6, IL-8, IL-17, CCL2, and TNF-α [ 162 ].…”